ACTR5 (ARP5) is a nuclear actin-related protein and an obligate subunit of the human INO80 ATP-dependent chromatin-remodelling complex. It belongs to the actin family, ARP5 subfamily: it retains the actin fold and an occupied nucleotide cleft -- ADP is resolved inside the ARP5 chain in three cryo-EM structures of the human complex -- but it has lost most of the actin ATP-hydrolysis machinery and the filament protomer interface, so it neither hydrolyses the bound nucleotide nor polymerises. Within INO80 it sits in the catalytic C-module alongside the Ino80 Snf2 motor, IES6/INO80C, IES2/INO80B and the RuvBL1-RuvBL2 heterohexamer, and it forms an obligate pair with IES6. Together they bind the nucleosome on the face opposite the motor domains, ARP5's DNA-binding domain gripping the nucleosomal DNA phosphate backbone in the minor groove around superhelical location -2 to -3. That grip is the anchor against which the motor pumps DNA, and it is what couples ATP hydrolysis to directional nucleosome sliding rather than to futile turnover; ARP5 also binds free H2A-H2B dimers in vitro. Human ARP5 has a much smaller insertion domain than its fungal counterparts and lacks the foot that grips the H2A/H2B acidic patch, so its nucleosome engagement is predominantly DNA-mediated. Through INO80, ARP5 acts in transcriptional regulation, DNA replication and DNA repair; its own loss-of-function phenotypes include impaired removal of UV photolesions, to which it is recruited before incision and where it interacts with DDB1, and impaired growth and gamma-H2AX accumulation after double-strand break induction, with reduced chromatin-bound INO80. It is predominantly nuclear, excluded from nucleoli and released from chromosomes as mitosis progresses, but shuttles between nucleus and cytoplasm. In hepatocellular carcinoma cells ARP5 occupies the CDKN2A promoter and is required to keep it silenced, sustaining CDK/E2F-driven proliferation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006338 chromatin remodeling | IBA GO_REF:0000033 | ACCEPT | Summary: Correct and core: ACTR5 is an obligate subunit of the catalytic C-module of INO80, and every ortholog donating this term carries its own experimental evidence for it. Reason: Every resolvable WITH/FROM token on this row is a reviewed Swiss-Prot ARP5 ortholog -- fly Arp5 (Q9VEC3), fission-yeast arp5 (Q9Y7X8), budding-yeast ARP5 (P53946) -- plus a self-reference. Queried individually in QuickGO, each donor holds its own experimental annotation in this branch (fly IMP PMID:16618800; pombe IDA PMID:19933844; yeast IDA x3 + IMP x2 + IPI), so no source-quality objection is available. ACTR5 also holds this term independently by IDA (PMID:21303910), and human ARP5 complements a yeast arp5 deletion, which is the biological warrant for the phylogenetic transfer. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0038576 · Arp5 (Q9VEC3), Drosophila melanogaster, Swiss-Prot SUPPORTS TRANSFER PANTHER:PTN000233752 · PANTHER tree node inside family PTHR11937 (ACTIN); an internal node, not a protein SUPPORTS TRANSFER PomBase:SPBC365.10 · arp5 (Q9Y7X8), Schizosaccharomyces pombe, Swiss-Prot SUPPORTS TRANSFER SGD:S000005004 · ARP5 (P53946), Saccharomyces cerevisiae, Swiss-Prot SUPPORTS TRANSFER UniProtKB:Q9H9F9 · ACTR5 itself: self-referential IBA, a PAINT curator judging the function core SUPPORTS TRANSFER Supporting Evidence: PMID:19014934 We show that human Arp5 (hArp5) proteins are localized in the nucleus, and that arp5Delta yeast cells are partially complemented by hArp5 PMID:21303910 ATP-dependent nucleosome remodeling by the hINO80 complex is catalyzed by a core complex comprising the hIno80 protein HSA/PTH and Snf2 ATPase domains acting in concert with YY1 and the complete set of its evolutionarily conserved subunits |
| GO:0030234 enzyme regulator activity | IBA GO_REF:0000033 | MODIFY | Summary: The regulatory relationship is real but the term names neither the enzyme nor the activity; replace with ATPase regulator activity plus, with contributes_to, the remodeler activity of the complex ACTR5 is part of. Reason: The single non-node donor is budding-yeast ARP5 (P53946), whose own IDA for this term (PMID:26306040) measured something specific: adding back the Arp5-Ies6 module stimulates the INO80 ATPase and nucleosome sliding, and an insertion-domain deletion uncouples the two. The regulated enzyme is therefore an ATP hydrolysis activity, which GO:0060590 ATPase regulator activity names and GO:0030234 does not. Hierarchy checked in QuickGO and confirmed in OLS rather than assumed: GO:0060590's only is_a parent is GO:0060589 nucleoside-triphosphatase regulator activity, which is_a GO:0030234, so GO:0060590 is a descendant two steps below the current term rather than a direct child; and GO:0001671 ATPase activator activity's only is_a parent is GO:0140677 molecular function activator activity, so GO:0001671 is not in the GO:0030234 branch at all, and moving there would leave the branch rather than refine within it. GO:0001671 is nevertheless the term the yeast add-back would license, and it is named here as the available alternative rather than dismissed: a curator who weights PMID:26306040's explicit stimulation result above the human coupling data should use it. This review prefers the direction-neutral GO:0060590 because the yeast result is an ectopic reconstitution add-back of the whole Arp5-Ies6 module, and because in human INO80 the mutations that break the ARP5/IES6-side nucleosome contacts lose sliding while retaining robust ATPase -- so what the human evidence isolates is coupling, not stimulation. GO:0140658 is added as a second replacement because a regulator term is arguably the wrong shape for an obligate subunit of the same complex: with contributes_to, GO:0140658 states ACTR5's participation in the machine's own catalytic activity, which PMID:21303910 shows requires the complete conserved subunit set. The donor is not weak -- it carries a real IDA -- so this is a term-scoping issue, not a source problem. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000233752 · PANTHER tree node inside family PTHR11937 (ACTIN); an internal node, not a protein SUPPORTS TRANSFER SGD:S000005004 · ARP5 (P53946), Saccharomyces cerevisiae, Swiss-Prot SUPPORTS TRANSFER Proposed replacements: ATPase regulator activity ATP-dependent chromatin remodeler activity Supporting Evidence: PMID:26306040 ectopic addition of the wild-type Arp5-Ies6 module stimulates INO80-mediated ATP hydrolysis and nucleosome sliding in vitro PMID:26306040 the addition of mutant Arp5 lacking unique insertion domains facilitates ATP hydrolysis in the absence of nucleosome sliding PMID:39676660 its necessity in linking INO80's ATPase activity to nucleosome movement PMID:29643506 The Arp5-Ies6 subunits couple ATP hydrolysis to nucleosome sliding in INO8010,19,20. |
| GO:0006355 regulation of DNA-templated transcription | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Defensible but broad and context-dependent: INO80 regulates transcription, and ACTR5 is required for the complex to work, but the sign of ACTR5's effect is locus-dependent and the activity is the complex's. Reason: Donors are fly Arp5 (IMP for this term, PMID:16618800, from the Pho-dINO80 complex study) and a self-reference standing on ACTR5's own GO:0045893 IMP. Both are sound, so the term is not wrongly transferred. It is kept as non-core because transcriptional regulation is downstream of what ARP5 itself does -- gripping nucleosomal DNA so that the Ino80 motor can reposition nucleosomes -- and because the only study that assayed ACTR5 at a promoter directly found it required for *silencing* CDKN2A (PMID:36563143), the opposite sign from the GO:0045893 row. The unsigned parent is thus the right level for a phylogenetic annotation, and no signed child should be inherited here. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: FB:FBgn0038576 · Arp5 (Q9VEC3), Drosophila melanogaster, Swiss-Prot SUPPORTS TRANSFER PANTHER:PTN000233752 · PANTHER tree node inside family PTHR11937 (ACTIN); an internal node, not a protein SUPPORTS TRANSFER UniProtKB:Q9H9F9 · ACTR5 itself: self-referential IBA, a PAINT curator judging the function core SUPPORTS TRANSFER Supporting Evidence: PMID:36563143 Furthermore, the presence of ACTR5 at the CDKN2A promoter region was confirmed by TST-mediated ChIP-seq and ChIP–quantitative polymerase chain reaction (qPCR) (Fig. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: The compartment is real -- hARP5 shuttles -- but is_active_in asserts that ACTR5 carries out its molecular function there, and nothing has ever been shown for the cytoplasmic pool beyond its existence in transit. Reason: This is a qualifier defect, not a term defect, and not a source defect. The donors are sound: Arabidopsis ARP5 (Q940Z2) has its own cytoplasm IDA (PMID:19679120) and ACTR5 has its own (PMID:19014934), reporting genuine nucleo-cytoplasmic shuttling of a predominantly nuclear protein. But is_active_in is the strong CC relation: it claims the gene product executes its MF in that compartment. Every characterised ARP5 activity is nuclear -- nucleosomal DNA binding at SHL -2/-3, assembly into the INO80 C-module, chromatin remodelling, the double-strand-break and UV-lesion phenotypes -- and no cytoplasmic activity, partner or complex has been reported for ARP5 in any organism. Recommended fix at node PTN000233752: change is_active_in to located_in. The two located_in cytoplasm rows are kept. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: AGI_LocusCode:AT3G12380 · ARP5 (Q940Z2), Arabidopsis thaliana, Swiss-Prot SUPPORTS SOURCE BUT NOT TARGET PANTHER:PTN000233752 · PANTHER tree node inside family PTHR11937 (ACTIN); an internal node, not a protein SUPPORTS SOURCE BUT NOT TARGET UniProtKB:Q9H9F9 · ACTR5 itself: self-referential IBA, a PAINT curator judging the function core SUPPORTS SOURCE BUT NOT TARGET Supporting Evidence: PMID:19014934 We show here that hArp5 shuttles between the nucleus and the cytoplasm PMID:41775336 ARP5 interacts with the phosphate backbone at the minor groove of DNA. |
| GO:0031011 Ino80 complex | IBA GO_REF:0000033 | ACCEPT | Summary: Correct and core: ARP5 is a conserved subunit of the INO80 complex in every organism where the complex has been purified, and each donor holds its own IDA or IPI for the complex. Reason: Four ARP5 orthologs plus a self-reference. Donor evidence queried individually: fly IDA + IPI, pombe IDA + IPI, budding yeast IDA x2 + IMP + IPI x2. Human ACTR5 additionally holds this term by IDA from two independent complex purifications (PMID:18026119, PMID:21303910), and subunit mapping places it specifically in the catalytic C-module with the Snf2 ATPase domain, IES2, IES6 and RuvBL1/2. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0038576 · Arp5 (Q9VEC3), Drosophila melanogaster, Swiss-Prot SUPPORTS TRANSFER PANTHER:PTN000233752 · PANTHER tree node inside family PTHR11937 (ACTIN); an internal node, not a protein SUPPORTS TRANSFER PomBase:SPBC365.10 · arp5 (Q9Y7X8), Schizosaccharomyces pombe, Swiss-Prot SUPPORTS TRANSFER SGD:S000005004 · ARP5 (P53946), Saccharomyces cerevisiae, Swiss-Prot SUPPORTS TRANSFER UniProtKB:Q9H9F9 · ACTR5 itself: self-referential IBA, a PAINT curator judging the function core SUPPORTS TRANSFER Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 PMID:41775336 INO80’s C-terminal region harbours the Snf2 domain (Ino80motor) and forms the nucleosome core particle mobilizing module along with nucleosome binding subunits ARP5 (actin-related protein 5), /IES6 (ino eighty subunit) subunit (INO80C), IES2 (INO80B), and the assembly chaperone heterohexamer AAA+ ATPases RuvBL1/RuvBL2 [28–30]. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Correct and core; a keyword-mapped restatement of ACTR5's own three nuclear IDAs. Reason: Derived from UniProt's Nucleus subcellular-location term, which is itself carried by ECO:0000269 evidence from PMID:18026119, PMID:18163988 and PMID:19014934. ACTR5's nuclear localisation is its own measurement, not a transfer -- worth stating because on ACTR10 the nucleus IBA turned out to be a paralog transfer from nuclear ARPs of a different subfamily and had to be removed. Nothing of that shape applies here. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0191 · UniProt Nucleus subcellular-location term, mapped by GO_REF:0000044 SUPPORTS TRANSFER |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Correct as a location but not where ACTR5 acts: the cytoplasmic pool is the shuttling intermediate of a predominantly nuclear protein. Reason: Mapped from UniProt's Cytoplasm subcellular-location term, which rests on PMID:19014934's demonstration of nucleo-cytoplasmic shuttling; UniProt itself notes that the protein is predominantly nuclear. located_in is the right relation here, in contrast to the is_active_in IBA row above. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0086 · UniProt Cytoplasm subcellular-location term, mapped by GO_REF:0000044 SUPPORTS TRANSFER Supporting Evidence: PMID:19014934 We show here that hArp5 shuttles between the nucleus and the cytoplasm |
| GO:0006259 DNA metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: True but vacuous: a top-level parent of terms ACTR5 already holds specifically, contributed by an ARBA rule with no gene-product source. Reason: ACTR5 already carries GO:0006302 double-strand break repair, GO:0070914 UV-damage excision repair, GO:0006275 regulation of DNA replication and GO:0060382 regulation of DNA strand elongation, all of which are descendants of GO:0006259. The row therefore adds no information and is not independent evidence -- ARBA rules are pattern-matched over existing annotation, so the parent is recovering what the children already assert. Propagation Review Root cause: EVIDENCE CIRCULAR OR REDUNDANT Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00028839 · ARBA machine-learning rule; no gene-product source available CIRCULAR OR REDUNDANT |
| GO:0033044 regulation of chromosome organization | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: An exact duplicate of the ComplexPortal IMP row for the same term, generated by an ARBA rule; it adds no evidence. Reason: ACTR5 holds GO:0033044 already, by IMP from PMID:26340092 via ComplexPortal. This ARBA row restates it from a machine-learning rule with no gene-product source, so it neither corroborates nor extends the claim. The substantive assessment of the term is on the IMP row, where the underlying experiment is INO80-complex knockdown. Propagation Review Root cause: EVIDENCE CIRCULAR OR REDUNDANT Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00029256 · ARBA machine-learning rule; no gene-product source available CIRCULAR OR REDUNDANT |
| GO:0051052 regulation of DNA metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: True but vacuous: the parent of the regulation-of-replication and strand-elongation terms ACTR5 already holds. Reason: GO:0006275 and GO:0060382, both already annotated to ACTR5, are descendants of GO:0051052. Same ARBA-rule provenance and same redundancy argument as the GO:0006259 row. Propagation Review Root cause: EVIDENCE CIRCULAR OR REDUNDANT Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00027282 · ARBA machine-learning rule; no gene-product source available CIRCULAR OR REDUNDANT |
| GO:0005515 protein binding | IPI PMID:16230350 A mammalian chromatin remodeling complex with similarities t... | MARK AS OVER ANNOTATED | Summary: Uninformative bare protein binding to an INO80 subunit detected by co-purification of the whole complex; the content is already carried by part_of GO:0031011. Reason: Bare GO:0005515 protein binding carries no functional information, and the information this row does carry -- that ACTR5 and ACTR8 (ARP8) are in the same assembly -- is already stated exactly by part_of GO:0031011 Ino80 complex, which ACTR5 holds with three IDAs. Multidimensional-protein-identification mass spectrometry of the whole hINO80 complex does not establish a direct ACTR5-ACTR8 (ARP8) contact: it establishes co-membership. Partner accession resolved to a reviewed Swiss-Prot canonical entry of the expected length, so this is not a wrong-partner problem, only an uninformative term. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 |
| GO:0005515 protein binding | IPI PMID:18163988 The actin-related protein hArp8 accumulates on the mitotic c... | KEEP AS NON CORE | Summary: A real, targeted binary interaction with a distinct biological point -- the ARP5-ARP8 association is present in interphase and lost in metaphase -- but protein binding is still an uninformative term. Reason: Unlike the whole-complex co-purifications, this is a hypothesis-driven reciprocal co-immunoprecipitation, and UniProt reads it as evidence that the INO80 complex may dissociate in mitosis. The same paper is the source of a useful negative for ACTR5: ARP8, not ARP5, accumulates on mitotic chromosomes, and ARP5 depletion does not misalign chromosomes -- so no chromosome-segregation function should be inferred for this gene. Kept as non-core because GO:0005515 names no activity; the functionally informative MF for ACTR5's role in the module is contributes_to GO:0031492 nucleosomal DNA binding, proposed below. Partner accession Q9H981 resolves to reviewed Swiss-Prot ACTR8, 624 aa, the canonical entry. Supporting Evidence: PMID:18163988 Here we report that hArp8, but not hArp5, accumulates on mitotic chromosomes PMID:18163988 depletion of hIno80 and hArp5 did not cause misalignment of chromosomes |
| GO:0005515 protein binding | IPI PMID:19014934 The human actin-related protein hArp5: nucleo-cytoplasmic sh... | MARK AS OVER ANNOTATED | Summary: Uninformative bare protein binding to an INO80 subunit detected by co-purification of the whole complex; the content is already carried by part_of GO:0031011. Reason: Bare GO:0005515 protein binding carries no functional information, and the information this row does carry -- that ACTR5 and INO80 are in the same assembly -- is already stated exactly by part_of GO:0031011 Ino80 complex, which ACTR5 holds with three IDAs. Co-immunoprecipitation of ACTR5 with the hIno80 holoenzyme does not establish a direct ACTR5-INO80 contact: it establishes co-membership. Partner accession resolved to a reviewed Swiss-Prot canonical entry of the expected length, so this is not a wrong-partner problem, only an uninformative term. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 |
| GO:0005515 protein binding | IPI PMID:20855601 INO80 chromatin remodeling complex promotes the removal of U... | KEEP AS NON CORE | Summary: The one partner outside the INO80 complex, and the one that carries functional information: DDB1 links ARP5 to UV-lesion recognition, matching the UV-damage excision repair IMP from the same study. Reason: DDB1 is not an INO80 subunit, so this row is not redundant with GO:0031011. IntAct records three assays for it from this single study -- anti-bait co-IP, anti-tag co-IP and pull-down -- i.e. genuine methodological redundancy rather than one screen counted several ways, and the interaction is functionally coherent with the same paper's finding that ARP5 deletion impairs removal of UV photolesions and that Arp5 is recruited to UV-damaged DNA before incision. Kept as non-core rather than modified because GO has no molecular-function term for this adaptor-like role, and the biology is already captured by GO:0070914. Partner accession Q16531 resolves to reviewed Swiss-Prot DDB1, 1140 aa, the canonical entry. Supporting Evidence: PMID:20855601 We showed that deletion of two core components of the INO80 complex, INO80 and ARP5, significantly hampered cellular removal of UV-induced photo lesions PMID:20855601 Ino80 and Arp5 are enriched to UV-damaged DNA in an NER-incision-independent fashion |
| GO:0005515 protein binding | IPI PMID:20855601 INO80 chromatin remodeling complex promotes the removal of U... | MARK AS OVER ANNOTATED | Summary: Uninformative bare protein binding to an INO80 subunit detected by co-purification of the whole complex; the content is already carried by part_of GO:0031011. Reason: Bare GO:0005515 protein binding carries no functional information, and the information this row does carry -- that ACTR5 and INO80 are in the same assembly -- is already stated exactly by part_of GO:0031011 Ino80 complex, which ACTR5 holds with three IDAs. Co-immunoprecipitation of ACTR5 with the INO80 holoenzyme does not establish a direct ACTR5-INO80 contact: it establishes co-membership. Partner accession resolved to a reviewed Swiss-Prot canonical entry of the expected length, so this is not a wrong-partner problem, only an uninformative term. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MARK AS OVER ANNOTATED | Summary: Uninformative bare protein binding to an INO80 subunit detected by co-purification of the whole complex; the content is already carried by part_of GO:0031011. Reason: Bare GO:0005515 protein binding carries no functional information, and the information this row does carry -- that ACTR5 and INO80C (IES6) are in the same assembly -- is already stated exactly by part_of GO:0031011 Ino80 complex, which ACTR5 holds with three IDAs. BAC-GFP affinity-purification mass spectrometry of the whole complex does not establish a direct ACTR5-INO80C (IES6) contact: it establishes co-membership. Partner accession resolved to a reviewed Swiss-Prot canonical entry of the expected length, so this is not a wrong-partner problem, only an uninformative term. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MARK AS OVER ANNOTATED | Summary: Uninformative bare protein binding to an INO80 subunit detected by co-purification of the whole complex; the content is already carried by part_of GO:0031011. Reason: Bare GO:0005515 protein binding carries no functional information, and the information this row does carry -- that ACTR5 and ACTR8 (ARP8) are in the same assembly -- is already stated exactly by part_of GO:0031011 Ino80 complex, which ACTR5 holds with three IDAs. BAC-GFP affinity-purification mass spectrometry of the whole complex does not establish a direct ACTR5-ACTR8 (ARP8) contact: it establishes co-membership. Partner accession resolved to a reviewed Swiss-Prot canonical entry of the expected length, so this is not a wrong-partner problem, only an uninformative term. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MARK AS OVER ANNOTATED | Summary: Uninformative bare protein binding to an INO80 subunit detected by co-purification of the whole complex; the content is already carried by part_of GO:0031011. Reason: Bare GO:0005515 protein binding carries no functional information, and the information this row does carry -- that ACTR5 and INO80 are in the same assembly -- is already stated exactly by part_of GO:0031011 Ino80 complex, which ACTR5 holds with three IDAs. BAC-GFP affinity-purification mass spectrometry of the whole complex does not establish a direct ACTR5-INO80 contact: it establishes co-membership. Partner accession resolved to a reviewed Swiss-Prot canonical entry of the expected length, so this is not a wrong-partner problem, only an uninformative term. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 |
| GO:0005515 protein binding | IPI PMID:29643506 Structure and regulation of the human INO80-nucleosome compl... | MARK AS OVER ANNOTATED | Summary: Uninformative bare protein binding to an INO80 subunit detected by co-purification of the whole complex; the content is already carried by part_of GO:0031011. Reason: Bare GO:0005515 protein binding carries no functional information, and the information this row does carry -- that ACTR5 and INO80 are in the same assembly -- is already stated exactly by part_of GO:0031011 Ino80 complex, which ACTR5 holds with three IDAs. Cryo-EM reconstruction of the INO80 holoenzyme (IntAct method: 3d-em) does not establish a direct ACTR5-INO80 contact: it establishes co-membership. Partner accession resolved to a reviewed Swiss-Prot canonical entry of the expected length, so this is not a wrong-partner problem, only an uninformative term. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: A single high-throughput two-hybrid screen logged three ways, pairing a nuclear chromatin-remodelling subunit with a desmosomal plakin cytolinker; no orthogonal assay and no follow-up. Reason: Querying IntAct directly for Q9H9F9 shows this interaction recorded under three method names from the same HuRI publication -- two hybrid array, two hybrid prey pooling approach and validated two hybrid -- which is where UniProt's NbExp=3 for PPL comes from. They are sub-methods of one experiment, not three experiments; the same trap was documented on ACRV1. Periplakin (O60437, reviewed, 1756 aa) is a plakin-family cytolinker of desmosomes and the cornified envelope, with no reported nuclear or chromatin function, and ACTR5 is a subunit of a nuclear remodelling complex. Nothing in ACTR5's own literature mentions periplakin. Marked as over-annotated rather than removed: an unreplicated screen hit is weak, not demonstrably false, and both accessions are canonical reviewed entries so there is no misidentification to argue from. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Uninformative bare protein binding to an INO80 subunit detected by co-purification of the whole complex; the content is already carried by part_of GO:0031011. Reason: Bare GO:0005515 protein binding carries no functional information, and the information this row does carry -- that ACTR5 and INO80C (IES6) are in the same assembly -- is already stated exactly by part_of GO:0031011 Ino80 complex, which ACTR5 holds with three IDAs. BioPlex affinity-purification mass spectrometry of the whole complex does not establish a direct ACTR5-INO80C (IES6) contact: it establishes co-membership. Partner accession resolved to a reviewed Swiss-Prot canonical entry of the expected length, so this is not a wrong-partner problem, only an uninformative term. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Uninformative bare protein binding to an INO80 subunit detected by co-purification of the whole complex; the content is already carried by part_of GO:0031011. Reason: Bare GO:0005515 protein binding carries no functional information, and the information this row does carry -- that ACTR5 and INO80 are in the same assembly -- is already stated exactly by part_of GO:0031011 Ino80 complex, which ACTR5 holds with three IDAs. BioPlex affinity-purification mass spectrometry of the whole complex does not establish a direct ACTR5-INO80 contact: it establishes co-membership. Partner accession resolved to a reviewed Swiss-Prot canonical entry of the expected length, so this is not a wrong-partner problem, only an uninformative term. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: Uninformative bare protein binding to an INO80 subunit detected by co-purification of the whole complex; the content is already carried by part_of GO:0031011. Reason: Bare GO:0005515 protein binding carries no functional information, and the information this row does carry -- that ACTR5 and INO80C (IES6) are in the same assembly -- is already stated exactly by part_of GO:0031011 Ino80 complex, which ACTR5 holds with three IDAs. OpenCell endogenous-tag pull-down of the whole complex does not establish a direct ACTR5-INO80C (IES6) contact: it establishes co-membership. Partner accession resolved to a reviewed Swiss-Prot canonical entry of the expected length, so this is not a wrong-partner problem, only an uninformative term. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: Uninformative bare protein binding to an INO80 subunit detected by co-purification of the whole complex; the content is already carried by part_of GO:0031011. Reason: Bare GO:0005515 protein binding carries no functional information, and the information this row does carry -- that ACTR5 and INO80 are in the same assembly -- is already stated exactly by part_of GO:0031011 Ino80 complex, which ACTR5 holds with three IDAs. OpenCell endogenous-tag pull-down of the whole complex does not establish a direct ACTR5-INO80 contact: it establishes co-membership. Partner accession resolved to a reviewed Swiss-Prot canonical entry of the expected length, so this is not a wrong-partner problem, only an uninformative term. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 |
| GO:0006275 regulation of DNA replication | IMP PMID:25016522 The mammalian INO80 chromatin remodeling complex is required... | KEEP AS NON CORE | Summary: A complex-level ComplexPortal projection: the cited study depleted INO80 and ARP8, and its cached full text does not mention ARP5 at all. Reason: This is a ComplexPortal annotation of CPX-846 (the INO80 chromatin remodeling complex) projected onto each subunit, not an experiment on ACTR5. The cited paper's full text is cached and contains zero occurrences of "Arp5" or "ACTR5" (case-insensitive grep = 0); the knockdowns were of INO80 and ARP8. So the directness implied by IMP does not hold for this gene, although the process assignment for the complex does. Retained rather than removed because projecting a complex-level process onto an obligate subunit is legitimate GO practice and ACTR5 is required for the complex's catalytic activity (PMID:21303910); marked non-core because the biology is INO80's, one step removed from ARP5's own molecular function. The evidence-code question -- IMP on a gene product that was not itself perturbed -- is raised once in suggested_questions rather than repeated per row. Supporting Evidence: PMID:25016522 INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication PMID:25016522 cells deficient for Ino80 and Arp8 had impaired replication restart after treatment with replication inhibitors |
| GO:0006338 chromatin remodeling | IDA PMID:21303910 Subunit organization of the human INO80 chromatin remodeling... | ACCEPT | Summary: Core: reconstituted subassemblies showed that ATP-dependent nucleosome remodelling by human INO80 requires the conserved subunit set that contains ARP5. Reason: The study dissected human INO80 into three modules and located ARP5 in the catalytic module with the Snf2 ATPase domain, IES2, IES6 and Tip49a/Tip49b, then showed by purification and assay of subassemblies that remodelling requires the complete set of evolutionarily conserved subunits. That is direct assay evidence for ARP5's participation, and it is corroborated mechanistically by the human cryo-EM structures, which place the ARP5-IES6 module on the nucleosome opposite the motor domains. Supporting Evidence: PMID:21303910 ATP-dependent nucleosome remodeling by the hINO80 complex is catalyzed by a core complex comprising the hIno80 protein HSA/PTH and Snf2 ATPase domains acting in concert with YY1 and the complete set of its evolutionarily conserved subunits PMID:29643506 The ARP5-IES6 module of INO80 makes additional contacts on the opposite side of the nucleosome |
| GO:0031011 Ino80 complex | IDA PMID:21303910 Subunit organization of the human INO80 chromatin remodeling... | ACCEPT | Summary: Core: ARP5 was identified in purified human INO80 and mapped to the catalytic C-module. Asserted twice in GOA for this reference (ComplexPortal and UniProt); reviewed once. Reason: Direct subunit assignment from purified complex and subassemblies. UniProt states the same placement, and the 2018 and 2026 cryo-EM structures resolve ARP5 as chain H or J of the human complex. Note that the GOA TSV carries this exact annotation twice for this reference, once from ComplexPortal and once from UniProt; the two rows are identical in every field the schema represents, so they are reviewed together here. Supporting Evidence: PMID:21303910 a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5 PMID:41775336 INO80’s C-terminal region harbours the Snf2 domain (Ino80motor) and forms the nucleosome core particle mobilizing module along with nucleosome binding subunits ARP5 (actin-related protein 5), /IES6 (ino eighty subunit) subunit (INO80C), IES2 (INO80B), and the assembly chaperone heterohexamer AAA+ ATPases RuvBL1/RuvBL2 [28–30]. |
| GO:0033044 regulation of chromosome organization | IMP PMID:26340092 Negative Regulation of p21Waf1/Cip1 by Human INO80 Chromatin... | KEEP AS NON CORE | Summary: A complex-level ComplexPortal projection from INO80-complex knockdown; plausible for the complex, but not an ARP5 measurement, and ARP5 depletion specifically does not disturb chromosome alignment. Reason: This is a ComplexPortal annotation of CPX-846 (the INO80 chromatin remodeling complex) projected onto each subunit, not an experiment on ACTR5. The cached record is abstract-only, and the abstract describes RNAi knockdown of INO80 and of "the INO80 complex", so which subunits were depleted cannot be checked from here and the curator's full-text reading is not second-guessed. It is worth recording alongside it that hARP5 depletion does not cause mitotic chromosome misalignment (PMID:18163988) -- a different aspect of chromosome biology from the abnormal chromosome stability reported here, but enough that no mitotic-segregation function should be read into this row. Retained rather than removed because projecting a complex-level process onto an obligate subunit is legitimate GO practice and ACTR5 is required for the complex's catalytic activity (PMID:21303910); marked non-core because the biology is INO80's, one step removed from ARP5's own molecular function. The evidence-code question -- IMP on a gene product that was not itself perturbed -- is raised once in suggested_questions rather than repeated per row. Supporting Evidence: PMID:26340092 RNAi knockdown strategies of INO80 not only led to prolonged progression of cell cycle phase G2/M to G1, but it also resulted in abnormal chromosome stability PMID:18163988 depletion of hIno80 and hArp5 did not cause misalignment of chromosomes |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:27641337 INO80 is required for oncogenic transcription and tumor grow... | KEEP AS NON CORE | Summary: A complex-level ComplexPortal projection from a study of INO80 and INO80B in lung cancer; the sign is not general, because the one study that assayed ACTR5 itself at a promoter found it required for silencing. Reason: This is a ComplexPortal annotation of CPX-846 (the INO80 chromatin remodeling complex) projected onto each subunit, not an experiment on ACTR5. The cached record is abstract-only and the abstract concerns Ino80 and Ino80B in non-small-cell lung cancer; ACTR5 is not named in it. Beyond the projection issue, the signed term is the reason this must not be read as ACTR5's general behaviour: PMID:36563143 ChIPed ACTR5 itself, found it at the CDKN2A promoter, and showed that knocking it down de-represses CDKN2A and reduces H3K9me2 there. A negative-regulation annotation is therefore proposed separately, and the two signs are locus-dependent rather than contradictory. Retained rather than removed because projecting a complex-level process onto an obligate subunit is legitimate GO practice and ACTR5 is required for the complex's catalytic activity (PMID:21303910); marked non-core because the biology is INO80's, one step removed from ARP5's own molecular function. The evidence-code question -- IMP on a gene product that was not itself perturbed -- is raised once in suggested_questions rather than repeated per row. Supporting Evidence: PMID:27641337 we show that the INO80 chromatin remodeling complex is required for oncogenic transcription and tumor growth in non-small-cell lung cancer PMID:36563143 Suppression of ACTR5 activated CDKN2A expression, ablated |
| GO:0051726 regulation of cell cycle | IMP PMID:26340092 Negative Regulation of p21Waf1/Cip1 by Human INO80 Chromatin... | KEEP AS NON CORE | Summary: A complex-level ComplexPortal projection; independently plausible for ACTR5 given its CDKN2A/E2F dependency in hepatocellular carcinoma, but not measured on ARP5 in the cited paper. Reason: This is a ComplexPortal annotation of CPX-846 (the INO80 chromatin remodeling complex) projected onto each subunit, not an experiment on ACTR5. The cited abstract reports prolonged G2/M-to-G1 progression after INO80 knockdown, not after ARP5 knockdown, and the cached record is abstract-only. There is separate, ACTR5-specific support for a cell-cycle role -- CRISPRi of ACTR5 de-represses CDKN2A and collapses the E2F programme in HepG2 cells (PMID:36563143) -- but that is cell-type-specific and is captured better by the proposed negative-regulation-of-transcription term than by this generic regulation-of-cell-cycle row. Retained rather than removed because projecting a complex-level process onto an obligate subunit is legitimate GO practice and ACTR5 is required for the complex's catalytic activity (PMID:21303910); marked non-core because the biology is INO80's, one step removed from ARP5's own molecular function. The evidence-code question -- IMP on a gene product that was not itself perturbed -- is raised once in suggested_questions rather than repeated per row. Supporting Evidence: PMID:26340092 RNAi knockdown strategies of INO80 not only led to prolonged progression of cell cycle phase G2/M to G1, but it also resulted in abnormal chromosome stability PMID:36563143 Suppression of ACTR5 activated CDKN2A expression, ablated |
| GO:0060382 regulation of DNA strand elongation | IMP PMID:25016522 The mammalian INO80 chromatin remodeling complex is required... | KEEP AS NON CORE | Summary: A complex-level ComplexPortal projection: replication elongation was assayed after depletion of INO80 and ARP8, and the paper's full text never mentions ARP5. Reason: This is a ComplexPortal annotation of CPX-846 (the INO80 chromatin remodeling complex) projected onto each subunit, not an experiment on ACTR5. Same reference and same limitation as the regulation-of-DNA-replication row: the cached full text contains zero occurrences of "Arp5" or "ACTR5", and the elongation defect was measured in INO80- and ARP8-deficient cells. The term is the more specific of the two and is a defensible complex-level statement. Retained rather than removed because projecting a complex-level process onto an obligate subunit is legitimate GO practice and ACTR5 is required for the complex's catalytic activity (PMID:21303910); marked non-core because the biology is INO80's, one step removed from ARP5's own molecular function. The evidence-code question -- IMP on a gene product that was not itself perturbed -- is raised once in suggested_questions rather than repeated per row. Supporting Evidence: PMID:25016522 INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication |
| GO:0005634 nucleus | EXP PMID:18163988 The actin-related protein hArp8 accumulates on the mitotic c... | ACCEPT | Summary: Core: hARP5 is nuclear in interphase cells, shown by imaging in the study that also established that it leaves chromosomes as mitosis progresses. Reason: UniProt cites this paper for ACTR5's nuclear localisation with ECO:0000269, and records from it that the protein is localised to interphase nuclei but not nucleoli and is excluded from chromosomes as mitosis progresses. Consistent with the other two nuclear IDAs and with the shuttling result. Supporting Evidence: PMID:18163988 Here we report that hArp8, but not hArp5, accumulates on mitotic chromosomes |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5689544 | ACCEPT | Summary: Correct and slightly more informative than nucleus: the Reactome reaction places the INO80 complex, and therefore ACTR5, in the nucleoplasm. Reason: R-HSA-5689544 is 'UCHL5 binds INO80 complex', a nucleoplasmic reaction, and UCHL5 association with human INO80 is experimentally established (PMID:18922472, cited by UniProt for ACTR5's presence in the complex). Compatible with every direct localisation result for ACTR5: interphase nuclei, excluding nucleoli. |
| GO:0005634 nucleus | IDA PMID:19014934 The human actin-related protein hArp5: nucleo-cytoplasmic sh... | ACCEPT | Summary: Core: direct localisation of human ARP5 to the nucleus in the paper dedicated to this protein. Reason: This is the gene's own characterisation paper. It reports nuclear localisation of hARP5 and functional complementation of a yeast arp5 deletion, establishing that the nuclear ARP function is conserved. This is ACTR5's own measurement, which is why the nucleus annotation here needs no phylogenetic support. Supporting Evidence: PMID:19014934 We show that human Arp5 (hArp5) proteins are localized in the nucleus, and that arp5Delta yeast cells are partially complemented by hArp5 |
| GO:0005737 cytoplasm | IDA PMID:19014934 The human actin-related protein hArp5: nucleo-cytoplasmic sh... | KEEP AS NON CORE | Summary: Correct: ACTR5 genuinely enters the cytoplasm, by nucleo-cytoplasmic shuttling. Non-core, because no ARP5 activity has been demonstrated there. Reason: The observation is direct and gene-specific, and UniProt records Cytoplasm for ACTR5 on this evidence while noting the protein is predominantly nuclear. It is recorded here rather than dismissed precisely because a divergent actin with a cytoplasm annotation is the shape of the ACTL8 propagation defect -- but this one is not a transfer, it is ACTR5's own result. Kept as non-core because the cytoplasmic pool is a transit pool; the reason the is_active_in IBA row is marked over-annotated is that it upgrades this same observation to a claim about where ACTR5 works. Supporting Evidence: PMID:19014934 We show here that hArp5 shuttles between the nucleus and the cytoplasm |
| GO:0006302 double-strand break repair | IMP PMID:19014934 The human actin-related protein hArp5: nucleo-cytoplasmic sh... | ACCEPT | Summary: ARP5-specific: RNAi depletion of hARP5 impairs growth and gamma-H2AX accumulation after double-strand break induction, and reduces chromatin-bound hIno80. Reason: One of only two process annotations on ACTR5 whose experiment was performed on ARP5 itself. The mechanism the authors propose is directly relevant to the molecular function proposed below: ARP5 depletion reduces chromatin-bound hIno80, so ARP5 contributes to engaging the complex with chromatin. UniProt cites this paper with ECO:0000269 for involvement in double-strand break repair. Accepted as stated; the measured readouts are a DNA-damage-response marker and post-damage growth rather than a repair-product assay, which is noted in knowledge_gaps rather than used to weaken a curator's experimental call. Supporting Evidence: PMID:19014934 after the induction of DNA double strand breaks (DSB), cell growth and the accumulation of phosphorylated histone H2AX (gamma-H2AX) are impaired by hArp5 depletion PMID:19014934 Association of hArp5 with the hIno80 chromatin remodeling enzyme and decrease of chromatin-bound hIno80 by hArp5-depletion indicate that hArp5 may have a role in the recruitment of the hINO80 complex to chromatin |
| GO:0070914 UV-damage excision repair | IMP PMID:20855601 INO80 chromatin remodeling complex promotes the removal of U... | ACCEPT | Summary: ARP5-specific: ARP5 deletion hampers removal of UV photolesions without affecting transcription of NER factors, and ARP5 is recruited to UV-damaged DNA before incision. Reason: The strongest process annotation on this gene. ARP5 is named as one of the two core components deleted, the defect is in lesion removal rather than in NER-factor expression, and ARP5 enrichment at UV-damaged DNA is incision-independent, placing it at damage recognition. The DDB1 interaction curated from the same study gives the row a physical partner consistent with lesion recognition. Supporting Evidence: PMID:20855601 We showed that deletion of two core components of the INO80 complex, INO80 and ARP5, significantly hampered cellular removal of UV-induced photo lesions PMID:20855601 Ino80 and Arp5 are enriched to UV-damaged DNA in an NER-incision-independent fashion |
| GO:0005634 nucleus | IDA PMID:18026119 A YY1-INO80 complex regulates genomic stability through homo... | ACCEPT | Summary: Core: independent direct evidence for nuclear ACTR5, from the study identifying the YY1-INO80 complex. Reason: UniProt cites this paper with ECO:0000269 for both ACTR5's nuclear localisation and its association with the INO80 complex. The cached record is abstract-only, and the abstract foregrounds YY1 and INO80 rather than ARP5, so the curator's full-text reading is relied on -- which is the normal situation for a complex-purification paper and not a curation error. The claim itself is corroborated by two other direct localisation results for this gene. Supporting Evidence: PMID:18026119 Functional assays revealed that both YY1 and INO80 are essential in homologous recombination-based DNA repair (HRR) |
| GO:0031011 Ino80 complex | IDA PMID:18026119 A YY1-INO80 complex regulates genomic stability through homo... | ACCEPT | Summary: Core: ACTR5 was identified in the purified YY1-INO80 complex, independently of the 2011 subunit-mapping study. Reason: A second, independent biochemical purification placing ARP5 in human INO80. UniProt records this reference for ACTR5's association with the INO80 complex with ECO:0000269. Together with PMID:21303910 and PMID:16230350 this makes complex membership the best-supported statement about the gene. |
| GO:0031492 nucleosomal DNA binding | IDA PMID:41775336 Recognition and remodelling of nucleosomes and hexasomes by ... | NEW | Summary: The molecular function the GO record omits entirely: ARP5's DNA-binding domain grips nucleosomal DNA in the minor groove at SHL -2/-3, the anchor point that lets INO80 convert ATP turnover into directional sliding. Reason: ACTR5's entire molecular-function record in GOA is one IBA to enzyme regulator activity plus fourteen rows of bare protein binding: there is no DNA-binding, nucleosome-binding or chromatin-binding term at all, even though the contact is resolved in human cryo-EM structures: the 2026 study reports overall map resolutions of 3.5-3.7 A for the states in which it describes this contact, and PDBe reports 3.35 A and 3.43 A for the two entries of that study in whose ARP5 chain a nucleotide is also modelled. ARP5's DBD contacts the nucleosomal DNA phosphate backbone in the minor groove, at SHL -3 in state N-7 and SHL -2 in state N-6, and near the dyad on the hexasome. GO:0031492 is the precise term: it is is_a GO:0031491 nucleosome binding, is_a GO:0003677 DNA binding and is_a GO:0003682 chromatin binding, so one specific term subsumes all three, and it correctly describes a sequence-independent backbone contact rather than a histone-surface contact -- which matters, because human ARP5 lacks most of the fungal grappler insertion that engages the H2A/H2B acidic patch. The qualifier is contributes_to, not enables, because the isolated protein does not bind nucleosomes at physiologically relevant concentrations without IES6; the functional unit is the ARP5-IES6 module. Note on the strength of the functional claim: the requirement of the conserved DBD loop residues for sliding was established in fungal INO80, not yet in human, so the human evidence here is the structural contact itself. Independently, budding-yeast ARP5 -- a WITH/FROM donor on four of ACTR5's five IBA rows -- already carries GO:0031491 by IDA (PMID:39676660), and that term has never propagated to any other ARP5 ortholog. Supporting Evidence: PMID:41775336 The DNA-binding domain (DBD) of ARP5 [30] interacts with nucleosomal DNA in the minor groove at SHL−3 in state N-7 and SHL−2 in state N-6, while it interacts with the hexasomal DNA at SHL+1 in state H-3 (Fig. PMID:41775336 ARP5 interacts with the phosphate backbone at the minor groove of DNA. PMID:41775336 As a consequence, the ARP5/IES6 subunits bind DNA on the opposite side of the hexasome near the dyad (SHL0) and SHL+1. PMID:29643506 b, A comparison of Arp5-Ies6 and Arp5 nucleosome binding activity assayed by EMSA, demonstrating a lack of nucleosome binding activity by Arp5 at in vivo relevant concentrations in the absence of Ies6. PMID:41775336 Previous studies with fungal INO80 have shown that the conserved DBD loop residues of ARP5 are essential for sliding activity of fungal INO80 on both nucleosomes and hexasomes [21, 30]. |
| GO:0043531 ADP binding | IDA PMID:41775336 Recognition and remodelling of nucleosomes and hexasomes by ... | NEW | Summary: ACTR5 has a real, occupied actin nucleotide cleft: ADP is modelled inside the ARP5 chain in three of the six deposited human INO80 structures, and the contacts map onto beta-actin's own ATP-contact positions. Reason: UniProt assigns ACTR5 to the actin family and CDD annotates cd10211 ASKHA_NBD_Arp5, but a fold name is not an activity, so this was tested rather than assumed. Analysis of the deposited coordinates (see the referenced RESULTS.md) finds ADP inside the chain that PDBe SIFTS maps to Q9H9F9 in 7ZI4 (3.2 A), 9GCG (3.43 A) and 9GE5 (3.35 A), with 16, 14 and 12 ARP5 residues within 4.0 A; ATP is never in the ARP5 chain. The reciprocal test -- do those observed contacts fall on ACTR5 positions that align to beta-actin's own ATP contacts in 2BTF? -- gives 13/16, 11/14 and 8/12, and the retained contacts are actin's two phosphate-binding loops and the adenosine shelf, so this is the canonical actin site rather than an adventitious surface. ADP is chosen over ATP because ADP is the species observed, following the same rule the ACTR1A and ACTR10 reviews applied. The obvious objection -- that every one of these samples was soaked with ADP-BeF3, so a modelled ADP might be half of an ATP mimic -- was tested and does not hold: in all three entries the ARP5 chain contains no BeF3, AlF, VO4 or PO4 group alongside its ADP, and in 7ZI4 the only BeF3 in the entire entry sits in chain G, the Ino80 motor, which is where an ATP mimic belongs. The soak therefore qualifies what the motor was trapped with, not what ARP5 holds. What the structures still cannot do is rank ADP against ATP, because no ATP was offered to ARP5 in solution; that limitation is in knowledge_gaps. The reference is PMID:41775336, which deposited 9GCG and 9GE5 and tabulates their ligand content; 7ZI4, the highest-resolution of the three, is an unpublished deposition, and the contact analysis itself is in the bioinformatics report quoted alongside. No ATP-hydrolysis term is proposed: only 2 of the 5 literature-defined actin catalytic positions survive in ACTR5 (D11 and H161 kept; Q137, D154, V159 lost), a result cross-checked against the independently committed ACTL7A audit, which computes the identical string. No ARP5 ortholog in any organism currently carries a nucleotide-binding term, so this is a family-level gap. Supporting Evidence: PMID:41775336 The structures were determined in the presence of the ATP analog ADP–BeF3 without any chemical crosslinking. file:human/ACTR5/ACTR5-bioinformatics/RESULTS.md **ADP is modelled in the ARP5 chain in 3 of 6 entries (7ZI4, 9GCG, 9GE5); ATP never is.** file:human/ACTR5/ACTR5-bioinformatics/RESULTS.md **The bound species is plain ADP, not an ATP analogue.** file:human/ACTR5/ACTR5-bioinformatics/RESULTS.md In 7ZI4 the only BeF3 in the whole entry sits in chain G, the Ino80 motor file:human/ACTR5/ACTR5-bioinformatics/RESULTS.md This is the actin nucleotide cleft, not an adventitious file:human/ACTR5/ACTR5-bioinformatics/RESULTS.md **ACTR5 = `DDSCH`, i.e. 2/5 conserved:** |
| GO:0042393 histone binding | IDA PMID:29643506 Structure and regulation of the human INO80-nucleosome compl... | NEW | Summary: Purified human ARP5 captures untagged H2A-H2B dimers in vitro, and yeast Arp5 binds free H2A-H2B dimers through a mapped hydrophobic/acidic patch distinct from the acidic-patch foot that human ARP5 lacks. Reason: Proposed with its limitations stated rather than suppressed. For: purified human ARP5 used as bait captures untagged H2A-H2B dimers, and IntAct curates ARP5-H2AC4 and ARP5-H2BC11 from this study. Corroborating and surface-localising: yeast Arp5 has two distinct nucleosome-proximal regions, and free-dimer binding maps to a hydrophobic/acidic Leu-Asp patch rather than to the arginine anchor that engages the nucleosome. Against, and the reason this is not offered as a core function: the human pull-down is n=1 at 20 uM bait and 40 uM prey, the adjacent panel of the same figure is the EMSA showing that ARP5 alone fails to bind nucleosomes at in-vivo-relevant concentrations, and human ARP5's insertion domain lacks the acidic-patch-binding foot that mediates the equivalent contact in fungal INO80, whose nucleosome recognition by this module is predominantly DNA-mediated. Those last two facts bound the claim but do not refute it: the foot binds the *nucleosome* acidic patch, a different surface from the free-dimer-binding patch the yeast work maps. Recorded as an annotation with the concentration, replication and surface-mapping gaps stated in knowledge_gaps. Supporting Evidence: PMID:29643506 Consistent with these contacts, Arp5 binds to H2A/H2B dimers in solution and the Arp5-Ies6 complex binds to nucleosomes (Extended Data Fig. PMID:29643506 a, Actin and Actin-related proteins were all expressed with a C-terminal double-Strep tag and used as bait to capture untagged H2A-H2B dimers. PMID:39676660 The other region has a hydrophobic/acid patch of Leu and Asp that binds free histone H2A-H2B dimers PMID:41775336 Human ARP5 has a much smaller insertion domain that particularly lacks the acidic patch binding foot. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:36563143 ACTR5 controls CDKN2A and tumor progression in an INO80-inde... | NEW | Summary: The only study to assay ACTR5 itself at a promoter found the opposite sign to the annotation GOA carries: ACTR5 occupies the CDKN2A promoter and is required to keep it silenced in hepatocellular carcinoma cells. Reason: GOA gives ACTR5 GO:0045893 positive regulation of DNA-templated transcription, projected from a study of INO80 and INO80B in lung cancer, and nothing negative. This study ChIPed ACTR5 directly: ACTR5 is present at the CDKN2A promoter, CRISPRi knockdown of ACTR5 induces CDKN2A mRNA and protein, and H3K9me2 -- but not H3K27me3 -- falls at the CDKN2A TSS on ACTR5 depletion. CDKN2A is RNA-polymerase-II transcribed, so GO:0000122 is the right specificity. Caveats stated rather than hidden: the effect is HepG2/HCC-specific (it is absent in CDKN2A-null U87 cells), it rests on a single study, and that study carries a 2025 erratum (PMID:41071901) correcting Fig. 2D -- the CDKN2A western -- because the ACTR5 and U87 panels had been duplicated from Fig. 3A; the publisher states the conclusions are unaffected, and the RNA-seq, ChIP-qPCR and H3K9me2 evidence is independent of the corrected panel. Read together with the GO:0045893 row, the conclusion is that the sign of ACTR5's transcriptional effect is locus-dependent, and neither row should be taken as the gene's general behaviour. The same paper's INO80-independence claim is not adopted; see knowledge_gaps. Supporting Evidence: PMID:36563143 Furthermore, the presence of ACTR5 at the CDKN2A promoter region was confirmed by TST-mediated ChIP-seq and ChIP–quantitative polymerase chain reaction (qPCR) (Fig. PMID:36563143 Our results revealed a significant reduction of H3K9me2 but not H3K27me3 at the CDKN2A TSS locus upon ACTR5 depletion (Fig. PMID:36563143 Suppression of ACTR5 activated CDKN2A expression, ablated file:human/ACTR5/ACTR5-deep-research-affinage.md ACTR5, a component of the INO80 chromatin remodeling complex, is essential for hepatocellular carcinoma (HCC) tumor progression; its suppression activates CDKN2A expression and ablates CDK/E2F-driven cell cycle signaling, attenuating HCC tumor growth. |
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Download this section (compressed HTML)Q: PAINT recommendation for node PTN000233752 (ARP5 subfamily within PTHR11937), stated once for the whole node rather than per gene. Three changes are warranted. (1) The GO:0005737 cytoplasm annotation should carry located_in, not is_active_in: the compartment is real for ACTR5 and for Arabidopsis ARP5, but no ARP5 molecular function has been demonstrated outside the nucleus in any organism. (2) A nucleosome-binding molecular function should propagate from this node: budding-yeast ARP5 (SGD:S000005004), a WITH/FROM donor on four of ACTR5's five IBA rows, carries GO:0031491 nucleosome binding by IDA (PMID:39676660), yet no other ARP5 ortholog has received it, and human ACTR5 has its own direct structural evidence for the more specific GO:0031492 nucleosomal DNA binding. (3) A nucleotide-binding molecular function is missing family-wide: checked in QuickGO, none of human ACTR5, fly Arp5, budding-yeast ARP5, fission-yeast arp5 or Arabidopsis ARP5 carries any term under GO:0000166, despite the ASKHA_NBD_Arp5 fold and ADP resolved in the ARP5 chain of three human INO80 structures. That third gap is the same one the ACTR1A, ACTR1B and ACTR10 reviews reported independently for the dynactin ARPs, which suggests it is systematic across the actin family rather than specific to ARP5.
Suggested experts: GO_Central PAINT curators, PANTHER
Q: ComplexPortal projects complex-level annotations onto every subunit while retaining the original evidence code. Five of ACTR5's rows are IMP on experiments in which ACTR5 was not the perturbed gene product; for PMID:25016522 this is verifiable, because the cached full text contains zero occurrences of "Arp5" or "ACTR5" and the knockdowns were of INO80 and ARP8. Should such projections carry IC (inferred by curator) with the complex as the with/from, reserving IMP for subunits that were themselves perturbed? The projections themselves look right; only the evidence code overstates directness.
Suggested experts: ComplexPortal, GO Consortium evidence-code working group
Q: Is GO:0030234 enzyme regulator activity, or any of its descendants, the right shape for a subunit that regulates the catalytic subunit of its own complex? ARP5 is not a separate factor acting on INO80; it is part of INO80. This review keeps a regulator term (refined to GO:0060590 ATPase regulator activity, which the donor's own IDA supports) and adds contributes_to GO:0140658, but GO may prefer only the latter. A general convention would help, because the same question arises for IES2/INO80B and for the RuvBL1/2 module.
Suggested experts: GO Consortium molecular-function working group
Q: Human ARP5 lacks the fungal grappler's acidic-patch-binding foot, and human INO80 nonetheless slides both nucleosomes and hexasomes, with only reduced rather than abolished dependence on the H2A acidic patch. Has the anchoring role of the ARP5 insertion domain been redistributed in metazoans -- to IES2's arginine anchor, or to the DNA-mediated ARP5/IES6 contacts -- and does that change which nucleosome substrates human INO80 can act on?
Suggested experts: Chromatin remodelling structural biologists
Q: ARP5 interacts with DDB1 and is recruited to UV-damaged DNA before incision. Is that recruitment DDB1/UV-DDB-dependent, and does ARP5's nucleosomal-DNA grip participate in exposing the lesion, or only in repositioning nucleosomes after recognition? This would decide whether a damage-recognition term, as well as GO:0070914, is warranted.
Suggested experts: Nucleotide excision repair community
Experiment: Reconstitute human INO80 with ARP5 carrying substitutions of the DBD loop residues identified in the 2026 nucleosome and hexasome structures, and assay nucleosome and hexasome sliding and ATPase side by side, using the published IES6 G135A/K136A/K137A mutant as an internal positive control. A sliding defect with retained ATPase would validate contributes_to GO:0031492 functionally, not just structurally.
Hypothesis: Human ARP5's DBD loop residues that contact nucleosomal DNA in the minor groove at SHL -2/-3 are required for INO80 nucleosome sliding, as their fungal equivalents are.
Type: structure-function mutagenesis with in vitro remodelling assays
Experiment: Measure nucleotide content and exchange kinetics on purified human ARP5 and ARP5-IES6 (HPLC or fluorescent nucleotide analogues), test for ATP hydrolysis with and without nucleosomes, and determine a structure from a preparation with no nucleotide analogue in the buffer. Compare thermal stability of wild-type ARP5 with substitutions in the phosphate-binding loops (G38/S39/R43) predicted from the alignment to beta-actin.
Hypothesis: The ADP in ACTR5's actin cleft is structural rather than catalytic: it does not turn over, and its loss destabilises the protein rather than abolishing an activity.
Type: biochemistry and cryo-EM
Experiment: Quantify ARP5 and ARP5-IES6 binding to H2A-H2B dimers by MST or ITC across a sub-micromolar to micromolar range, then mutate the candidate patch identified by aligning human ARP5 to the yeast region. Include the nucleosome EMSA from the same figure as the concentration control, so the affinity is interpreted against a known threshold.
Hypothesis: Human ARP5 binds H2A-H2B through the surface equivalent to the hydrophobic/acidic Leu-Asp patch mapped in yeast Arp5, and does so at physiological concentrations.
Type: quantitative binding assays with targeted mutagenesis
Experiment: In HepG2 cells, size-fractionate nuclear extract and ask whether any ARP5-IES6 species elutes free of the Ino80 motor and RuvBL1/2 (crosslinking mass spectrometry on the fractions). Then test whether the ARP5 requirement for proliferation survives acute degron depletion of the Ino80 ATPase. Absence of a free module plus loss of the ARP5 requirement on Ino80 depletion would settle the question against INO80-independence.
Hypothesis: ARP5 and IES6 do not exist as a functional module outside the INO80 complex, so the reported HepG2-selective dependency reflects differential redundancy rather than an INO80-independent activity.
Type: biochemical fractionation plus degron genetics
Experiment: Run homologous-recombination (DR-GFP) and end-joining (EJ5-GFP) reporter assays in ARP5-depleted cells, with rescue by wild-type ARP5 and by a DBD-loop mutant. Read out repair efficiency rather than gamma-H2AX, so that signalling and repair are separated.
Hypothesis: ARP5's role in the double-strand break response is repair, not only damage signalling.
Type: DNA repair reporter assays with structure-guided rescue
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The surface by which human ARP5 binds H2A-H2B, and whether that binding occurs at physiological concentrations, are undetermined.
OPEN BIOLOGY MF_DARK
What is known: Purified human ARP5 does capture untagged H2A-H2B dimers in vitro, and yeast Arp5 binds free H2A-H2B dimers through a mapped hydrophobic/acidic Leu-Asp patch. What is not established for human ARP5 is which residues mediate it: human ARP5's insertion domain lacks the acidic-patch-binding foot present in fungal Arp5, the human pull-down is a single experiment at 20 uM bait and 40 uM prey, and the adjacent panel of the same figure shows ARP5 alone fails to bind nucleosomes at in-vivo-relevant concentrations.
Significance: It decides whether GO:0042393 histone binding is a genuine molecular function of human ARP5 or an artefact of high-concentration in vitro capture, and whether human INO80 retains any histone-surface engagement by this subunit at all.
What would resolve it: Quantitative binding of human ARP5 and ARP5-IES6 to H2A-H2B at sub-micromolar concentrations, with mutagenesis of the candidate hydrophobic/acidic patch identified in yeast.
Provenance (the field's own admissions):
Gap: Whether the nucleotide in ACTR5's actin cleft exchanges, is hydrolysed, or is structural is untested.
OPEN BIOLOGY MF_DARK
What is known: Occupancy is established: ADP is modelled in the ARP5 chain of three human INO80 depositions and the contacts map onto beta-actin's own ATP-contact positions; the bound species is plain ADP -- no BeF3, AlF, VO4 or PO4 sits in the ARP5 chain in any of the three entries, and in 7ZI4 the only BeF3 in the entry is in the Ino80 motor chain. What is untested is turnover: no ATP was offered to ARP5 in solution, so no ADP-versus-ATP preference has been measured, and only 2 of the 5 literature-defined actin catalytic positions survive, which argues against hydrolysis but does not measure exchange.
Significance: If the nucleotide is structural rather than catalytic, ARP5's cleft is a folding/stability determinant, which would explain why five of the six CRISPR-hypersensitive regions of ACTR5 map to its structural backbone rather than to a surface.
What would resolve it: Nucleotide-exchange and ATPase assays on purified human ARP5 and ARP5-IES6, and a structure determined without a nucleotide analogue in the buffer.
Provenance (the field's own admissions):
Gap: Whether ACTR5 and IES6 have a function outside the INO80 complex is unresolved, and the published claim that they do is not adopted here.
OPEN BIOLOGYCURATION BP_DARK
What is known: What is established is a selective dependency: CRISPR tiling of ACTR5 finds HepG2-selective essential regions where tiling of INO80, MCRS1, ACTR8 and YY1 does not, and deleting the surface region A5 (G502-S519) abolishes both the proliferation requirement and the IES6 interaction. What is not established is INO80-independence: the argument rests on the *absence* of a HepG2-selective domain in the other subunits, differential CRISPR dependency can reflect differential redundancy rather than complex-independence, and the one requirement actually mapped runs through IES6, which is itself an INO80 subunit (INO80C).
Significance: An INO80-independent ARP5-IES6 activity would be a new chromatin-regulatory entity and would change how every complex-level annotation on this gene should be read; on the present evidence no such annotation is warranted.
What would resolve it: Size-fractionation or crosslinking mass spectrometry showing an ARP5-IES6 species free of the Ino80 motor and RuvBL1/2, plus a genetic test that the HepG2 requirement survives depletion of the Ino80 ATPase.
Provenance (the field's own admissions):
Gap: No human ARP5 point mutant has been tested for nucleosome sliding, so ARP5's DNA-contact residues are structurally identified but functionally untested in human INO80.
OPEN BIOLOGY MF_DARK
What is known: The contact itself is resolved in human structures, and the equivalent DBD loop residues are known to be essential for sliding in fungal INO80. The human functional test has not been done; in the 2026 study the mutants made were in IES6 and in the H2A acidic patch, not in ARP5.
Significance: It would convert the proposed contributes_to GO:0031492 annotation from a structural observation into a functionally validated one, and would test whether human INO80 tolerates loss of the ARP5 grip better than fungal INO80 does, as the reduced acidic-patch dependence of human sliding suggests.
What would resolve it: Sliding and ATPase assays on human INO80 reconstituted with ARP5 DBD-loop substitutions, alongside the IES6 GKK mutant as an internal control.
Provenance (the field's own admissions):
Gap: Whether ARP5 acts in double-strand break repair itself, or in the damage signalling that precedes it, is not separated by the existing data.
OPEN BIOLOGYCURATION BP_DARK
What is known: ARP5 depletion impairs post-damage growth and gamma-H2AX accumulation, and reduces chromatin-bound INO80, so ARP5 is required for the chromatin response to breaks. gamma-H2AX accumulation is a damage-signalling readout, not a measure of repair-product formation, and no repair-efficiency assay (homologous recombination or non-homologous end joining reporter) has been reported for ARP5 depletion specifically.
Significance: It determines whether GO:0006302 double-strand break repair is the right term for ARP5 or whether a DNA-damage-response term would be more accurate; the existing IMP is accepted here rather than second-guessed.
What would resolve it: Homologous-recombination and end-joining reporter assays in ARP5-depleted cells, with rescue by wild-type and DBD-mutant ARP5.
Provenance (the field's own admissions):
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