DNASE1L3 is a calcium- and magnesium-dependent DNase I-family endonuclease that degrades extracellular DNA, including nucleosomal chromatin associated with apoptotic cell-derived microparticles and released neutrophil extracellular traps. It shapes the size of circulating plasma DNA, and it clears DNA tethered to the outer surface of some cells by heparan sulfate proteoglycans and cell surface proteins, where the tethered DNA is of mitochondrial origin and carries oxidative damage. On B cells, surface DNA is removed by the secreted enzyme and not by DNASE1. Its C-terminal region supports access to protein- and lipid-associated DNA substrates, helping clear self-DNA and limit anti-DNA autoimmunity. Intracellular DNASE1L3 can also cleave nuclear chromatin into internucleosomal fragments in dying cells; this contribution depends on the cellular and death-induction context.
Definition: The disaggregation of a neutrophil extracellular trap, including breakdown of its extracellular DNA scaffold.
Justification: Current searches distinguish NET formation (GO:0140645) and symbiont-mediated NET disruption (GO:0141144), but did not identify a host NET-disassembly term. PMID:29191910 directly demonstrates host DNase-mediated digestion after NET release. This ontology proposal records that distinction; it does not add a new annotation or substitute formation for degradation. Parent placement requires ontology review.
Supporting Evidence:
Definition: The chemical reactions and pathways resulting in the breakdown of DNA located outside the cell, including cell-free plasma DNA, DNA in membrane vesicles and microparticles, the DNA scaffold of extracellular traps, and DNA tethered to the outer cell surface.
Justification: GO locates DNA breakdown only inside the cell. Mitochondrial DNA catabolic process (GO:0032043) is defined as DNA catabolic process occurring in the mitochondrion, so it cannot describe extracellular breakdown of DNA of mitochondrial origin. Checked against the repository's pinned GO build rather than asserted, and re-runnable as 'runoak -i sqlite:obo:go descendants -p i,p GO:0006308', which returns four lines including the root. DNA catabolic process (GO:0006308) has exactly three live is_a/part_of descendants, and none is extracellular. They are apoptotic DNA fragmentation (GO:0006309), mitochondrial DNA catabolic process (GO:0032043) and spermatid mitochondrial nucleoid elimination (GO:7770014). The former endonucleolytic and exonucleolytic children (GO:0000737, GO:0000738) are obsolete, which is why they do not appear. Secreted DNASE1L3 digests circulating plasma DNA, microparticle chromatin, released NETs and DNA tethered to the outer cell surface; loss causes human SLE. A child of GO:0006308 located in the extracellular region would capture this, and would also serve DNASE1. A further child, cell surface DNA catabolic process, could be added if more surface-DNA nucleases are found.
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002283 neutrophil activation involved in immune response | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Extracellular NET digestion does not establish neutrophil activation. Reason: The mouse source and its O55070 transfer positively establish digestion of already released NETs. In PMID:29191910, G-CSF supplies the neutrophilic stimulus, while restored circulating DNase prevents NET-clot obstruction. Assigning GO:0002283 overextends that clearance mechanism to a change in neutrophil activation. Supplementary methods remain inaccessible, but this judgment concerns the demonstrated step, not a claim that DNASE1L3 can never influence activation. Supporting Evidence: |
| GO:0002283 neutrophil activation involved in immune response | ISS PMID:29191910 Host DNases prevent vascular occlusion by neutrophil extrace... | MARK AS OVER ANNOTATED | Summary: Extracellular NET digestion does not establish neutrophil activation. Reason: The mouse source and its O55070 transfer positively establish digestion of already released NETs. In PMID:29191910, G-CSF supplies the neutrophilic stimulus, while restored circulating DNase prevents NET-clot obstruction. Assigning GO:0002283 overextends that clearance mechanism to a change in neutrophil activation. Supplementary methods remain inaccessible, but this judgment concerns the demonstrated step, not a claim that DNASE1L3 can never influence activation. Supporting Evidence: |
| GO:0002673 regulation of acute inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NET digestion provides a context-specific inflammatory regulatory role. Reason: The O55070 transfer is grounded in mouse NET-clearance experiments. Enzymatic removal of extracellular chromatin limits inflammatory vascular injury, supporting this broad regulatory term without making it a separate core activity. A narrower negative-regulation assignment is not made: the intervention protects against NET-clot injury during ongoing neutrophilia, without resolving a specific reduction in neutrophil activation or the entire acute inflammatory response. Supporting Evidence: |
| GO:0002673 regulation of acute inflammatory response | ISS PMID:29191910 Host DNases prevent vascular occlusion by neutrophil extrace... | KEEP AS NON CORE | Summary: Retain the experimentally grounded inflammatory context. Reason: Mouse loss and re-expression experiments support regulation through NET digestion. Human clinical plasma observations are corroborative, not an isolated human DNASE1L3 assay. A narrower negative-regulation assignment is not made: the intervention protects against NET-clot injury during ongoing neutrophilia, without resolving a specific reduction in neutrophil activation or the entire acute inflammatory response. Supporting Evidence: |
| GO:0003677 DNA binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: DNA substrate recognition is supported within the nuclease function. Reason: The literal PTN000889801 DNA-binding IBD is on the human Q13609 lineage; the current family alignment exactly reconstructs the 305-residue sequence. Rat O89107 has an experimental DNA-binding record. This is credible ancestral grounding, not a donor-count argument. Retain substrate binding without assigning a separate DNA-binding core. |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat ortholog supports DNA recognition associated with catalysis. Reason: O89107 is the verified rat DNASE1L3 ortholog and carries the experimental DNA-binding assertion from PMID:9665719. Its complete abstract reports a chromatin-associated nuclease; full methods remain unavailable. Independent human DNA-hydrolysis experiments corroborate the biological claim, while no sequence-selective binding function is inferred. |
| GO:0003677 DNA binding | TAS PMID:9070308 Cloning and characterization of a novel human DNase. | KEEP AS NON CORE | Summary: DNA binding is part of substrate handling by this nuclease. Reason: The complete source abstract positively reports purified recombinant human enzyme and DNA hydrolysis. Retain the curatorβs binding assertion as substrate recognition, corroborated by the human chromatin-substrate experiments in PMID:27293190; no independent sequence-specific recognition or regulatory DNA-binding role is asserted. |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: Use the established specific DNase I activity. Reason: The target contains IPR005135 and the current InterPro mapping does emit catalytic activity. The broad domain does not establish a different reaction. Specific DNase I activity is supported by the verified PAINT lineage and human recombinant endonuclease chemistry, making GO:0004530 an evidence-backed descendant. Proposed replacements: deoxyribonuclease I activity |
| GO:0004519 endonuclease activity | IEA GO_REF:0000107 | MODIFY | Summary: Refine ortholog-derived endonuclease activity to DNase I activity. Reason: Mouse O55070 has a positive endonuclease donor assertion from PMID:12050166. Human biochemical evidence and the on-lineage DNase I IBD support the more specific DNA-cleaving activity; this does not infer RNA cleavage from the broader endonuclease label. Proposed replacements: deoxyribonuclease I activity |
| GO:0004520 DNA endonuclease activity | IEA GO_REF:0000107 | MODIFY | Summary: DNase I activity is the supported specific DNA endonuclease function. Reason: Rat O89107 provides positive experimental nuclease grounding, and the human protein is independently a Ca/Mg-dependent DNase I-family endonuclease. The current typed ontology places GO:0004530 below GO:0004520. Proposed replacements: deoxyribonuclease I activity |
| GO:0004530 deoxyribonuclease I activity | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited DNase I chemistry is experimentally corroborated. Reason: The PTN000889801 assertion is ancestral to the actual human leaf in PTHR11371, with experimental DNase I family descendants. The human recombinant DNase study explicitly reports DNA hydrolysis producing 3β²-OH/5β²-P ends. This agrees with the inherited chemistry without treating family assignment alone as an assay. Supporting Evidence: PMID:11141064 produce 3'-OH/5'-P ends. |
| GO:0004536 DNA nuclease activity | IEA GO_REF:0000120 | MODIFY | Summary: The combined electronic rule supports a more specific nuclease term. Reason: The current IPR016202 mapping and ARBA00027850 branch 19 match: official FunFam 3.60.10.10:FF:000007 plus Primates. They support DNA nuclease activity. Verified DNase I ancestry and human chemistry justify refinement to GO:0004530, a typed descendant, rather than leaving an unnecessarily broad MF. Proposed replacements: deoxyribonuclease I activity |
| GO:0004536 DNA nuclease activity | TAS PMID:9070308 Cloning and characterization of a novel human DNase. | MODIFY | Summary: Refine DNA nuclease activity using independently established chemistry. Reason: The cited abstract positively describes purified baculovirus-derived human protein that hydrolyzes DNA; its historical 306-residue sequence is not substituted for the current reference. Specific DNase I activity is independently corroborated by human endonuclease/end-product measurements and PAINT. Proposed replacements: deoxyribonuclease I activity |
| GO:0005509 calcium ion binding | TAS PMID:9205125 Identification, localization, and expression of two novel hu... | KEEP AS NON CORE | Summary: Retain calcium binding as a catalytic cofactor property. Reason: The original TAS source identifies conserved calcium-binding residues. Independent recombinant human Trx-DNase gamma assays in PMID:14646506 report Ca/Mg- or Mn-dependent chromatin cleavage, and PMID:10807908 supports the Ca/Mg-dependent nuclease and its regulation. These corroborate the catalytic cofactor property without supplying a calcium-binding affinity or separate calcium-sensor function. Both newly fetched caches contain abstracts only. Supporting Evidence: PMID:14646506 Ca(2+)/Mg(2+)- or Mn(2+)-dependent endonuclease activity that cleaves chromatin DNA to nucleosomal units. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: CYSRT1 binding is a supported non-core screen interaction. Reason: The exact HuRI pair is human Q13609βA8MQ03 (CYSRT1), with sequence-matched ROGIDs and array, pooling and validated-two-hybrid records. These support binding capacity of the tagged products in yeast. No physiological nuclease mechanism or more specific partner-class activity is established; retain the positive generic assertion under the scoped project instruction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: KRTAP5-9 binding is a supported non-core screen interaction. Reason: The exact HuRI pair is human Q13609βP26371 (KRTAP5-9), independently matched by sequence checksums and validated-two-hybrid records. KRTAP5-9 is a keratin-associated protein, not evidence that DNASE1L3 binds an assembled intermediate filament. Retain this positive binary-screen assertion as non-core under the scoped project instruction, without inventing a cytoskeletal activity. Supporting Evidence: |
| GO:0005576 extracellular region | EXP PMID:9714828 Cloning and characterization of an actin-resistant DNase I-l... | ACCEPT | Summary: Extracellular secretion is central to DNA clearance. Reason: The complete source abstract explicitly reports secreted mature human and mouse LS-DNase. Independent human-expression and plasma experiments demonstrate extracellular DNASE1L3 activity on chromatin substrates. The original secretion methods remain uninspected, but the positive claim is directly corroborated. Supporting Evidence: PMID:9714828 LS-DNase from both species is a secreted, non-glycosylated protein |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: The curated secreted-location mapping is biologically supported. Reason: UniProt SL-0243 maps to extracellular region, consistent with the human secretion report and extracellular human DNASE1L3 assays. There is no evidence here for a more precise universal extracellular compartment or stable cell-surface attachment. |
| GO:0005634 nucleus | EXP PMID:11141064 Characterization of human DNase I family endonucleases and a... | ACCEPT | Summary: Nuclear relocation is supported in an induced apoptotic context. Reason: The complete cited abstract reports nuclear relocation of human DNase gamma in transfected HeLa S3 cells after apoptosis induction. Independent endogenous HT-29 localization and human-construct DNA-fragmentation experiments support the nucleus as a site of the intracellular catalytic unit. The original expression/stimulation context and unavailable full text remain explicit; no constitutive or subnuclear localization is inferred. Supporting Evidence: PMID:11141064 to translocate into the nucleus during apoptosis. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: The ancestral nuclear localization has target and ortholog grounding. Reason: The imported PTN000889801 assertion lies on the human lineage and has genuine human and rodent experimental grounding, including the expected target self-source. Endogenous human nuclear relocation and human-construct chromatin cleavage establish a nuclear catalytic context. Accept the location for that unit without treating nuclear residence as constitutive or replacing extracellular clearance. |
| GO:0005634 nucleus | IDA PMID:23229555 Apoptotic DNA fragmentation may be a cooperative activity be... | ACCEPT | Summary: Endogenous HT-29 protein relocates to the nucleus after etoposide. Reason: Original immunofluorescence and fractionation with compartment controls show endogenous DNAS1L3 moving from ER to nucleus in etoposide-treated human HT-29 cells. Together with independent human-construct chromatin cleavage, this supports the nucleus as an activity location of the intracellular DNA-disposal unit. The observation remains conditional and does not resolve a nuclear subcompartment. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: The combined nuclear mapping reflects an experimentally supported pool. Reason: The recorded mouse-ortholog and UniProt SL-0191 routes are retained. Direct human localization and chromatin-cleavage evidence independently supports the nuclear catalytic unit, making this location core in that context. Neither the electronic mapping nor the synthesis establishes constitutive nuclear residence or a finer nuclear subcompartment. |
| GO:0005783 endoplasmic reticulum | IDA PMID:23229555 Apoptotic DNA fragmentation may be a cooperative activity be... | KEEP AS NON CORE | Summary: ER localization is supported in untreated human HT-29 cells. Reason: The originalβs endogenous staining and fractionation support an ER-associated pool before etoposide treatment. They do not resolve ER membrane versus lumen, so retain the measured organelle-level claim. ORGANELLES ER check (2026-11-05): the abstract states that endogenous DNAS1L3 localized to the ER in HT-29 cells and moved to the nucleus on apoptosis induction, so this is the endogenous protein in a native cell (the ADIPOQ case in ER batch 1), and the row stays KEEP_AS_NON_CORE rather than MARK_AS_OVER_ANNOTATED. The extracellular DNase activity of the secreted enzyme is the core function. No sub-compartment row is added: the cleaved signal peptide (UniProt SIGNAL 1..20) and soluble chain would put a resident pool in the lumen, but there is no KDEL-type retrieval motif (the basic C-terminal tail, residues 284-305, is the region UniProt notes by similarity as needed for activity on liposome-coated DNA; on a soluble chain it is not a di-lysine retention signal, which works only on cytosolic tails of membrane proteins), the protein is also secreted, and an ER-to-nucleus move during apoptosis argues against a simple lumenal pool. One line, with a disagreeing one, so it stays at the root. Supporting Evidence: PMID:23229555 In HT-29 cells, endogenous DNAS1L3 localized to the endoplasmic reticulum (ER) and translocated to the nucleus upon apoptosis induction but prior to INDF manifestation |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The curated ER mapping preserves the measured intracellular pool. Reason: UniProt SL-0095 corresponds to ER. The human cellular experiment supports this pool, without contradicting secretion or proving a specific ER subcompartment. ORGANELLES ER check (2026-11-05): the UniProt ER line is curated from PMID:23229555 (ECO:0000269), the same endogenous HT-29 result as the IDA row, so this row has the same action; see that row for why no lumen or membrane row is added. Supporting Evidence: PMID:23229555 In HT-29 cells, endogenous DNAS1L3 localized to the endoplasmic reticulum (ER) and translocated to the nucleus upon apoptosis induction but prior to INDF manifestation file:human/DNASE1L3/DNASE1L3-uniprot.txt Endoplasmic reticulum {ECO:0000269|PubMed:23229555} |
| GO:0006259 DNA metabolic process | TAS PMID:9070308 Cloning and characterization of a novel human DNase. | MODIFY | Summary: DNA catabolism captures the demonstrated metabolic direction. Reason: The source reports hydrolysis of DNA by purified human recombinant protein. Catabolism, rather than undifferentiated DNA metabolism, describes the performed reaction and is a verified typed descendant of GO:0006259. Proposed replacements: DNA catabolic process Supporting Evidence: |
| GO:0006308 DNA catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: DNA breakdown is the common process across demonstrated substrates. Reason: The IPR016202 mapping and mouse ortholog route are reproduced, and direct human assays establish DNA degradation. Retain the broad catabolic process because extracellular chromatin clearance is not exhausted by the narrower apoptotic-fragmentation annotation. PMID:42838054 adds a further extracellular substrate, reporting that human and murine B cell surfaces carry DNA cleared by the secreted nuclease and that patients with a DNASE1L3 missense variant hold more surface DNA on B and T cells. The comparator result that recombinant DNASE1L3 but not DNASE1 removes it, and the identity of the variant as R206C, are read from the open preprint PMID:41280093 rather than from the published abstract. The mitochondrial origin of surface DNA was established in cell lines, so this row rests on extracellular DNA breakdown and not on a mitochondrial substrate identity at B cells. GO:0032043 mitochondrial DNA catabolic process would not fit either way; its logical definition is DNA catabolic process occurring in the mitochondrion, whereas this DNA is degraded outside the cell. GO has no extracellular DNA catabolic term (see proposed_new_terms). The action stays ACCEPT rather than a MODIFY onto that proposed term because the nuclear core function also needs the general term, so replacing it here would leave that activity without a process. Supporting Evidence: PMID:42838054 human and murine B cell surfaces contain DNA that can be cleared by the secreted nuclease DNASE1L3 PMID:41280093 DNASE1L3, but not DNASE1, partially and reproducibly removed cell surface DNA |
| GO:0006309 apoptotic DNA fragmentation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain inherited apoptotic-fragmentation capacity with context limits. Reason: PTN000146474 lies on the human lineage and is grounded by human and mouse experiments. Positive human-construct cooperation with CAD supports capacity in the tested system. The later necrosis study limits universality rather than falsifying every apoptotic context. |
| GO:0006309 apoptotic DNA fragmentation | IDA PMID:23229555 Apoptotic DNA fragmentation may be a cooperative activity be... | KEEP AS NON CORE | Summary: Human DNAS1L3 can cooperate with CAD in induced DNA fragmentation. Reason: Human DNAS1L3 expression in mouse MEFs restored TNF/CHX-associated internucleosomal fragmentation only with competent ICAD/CAD. This supports a conditional catalytic contribution, not autonomous apoptosis initiation or universal requirement. Distinct later necrosis experiments caution against reading every DNA ladder as apoptosis. Supporting Evidence: PMID:23229555 These results suggest a cooperative activity between CAD and DNAS1L3 to accomplish INDF. |
| GO:0010623 programmed cell death involved in cell development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain the inherited developmental context with its mouse donor scope. Reason: The actual PTN000146474 IBD is on the target lineage. Its mouse donor study positively reports differentiation-associated nuclease induction, ectopic activity and antisense-sensitive DNA fragmentation in C2C12 cells. Full original methods remain inaccessible, so no human developmental assay is claimed. This is a credible context-specific inherited assertion, not a separate developmental core. Supporting Evidence: |
| GO:0070948 regulation of neutrophil mediated cytotoxicity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: NET-clot clearance does not establish directed neutrophil target-cell killing. Reason: PMID:29191910 shows extracellular DNA digestion and protection from vascular obstruction, erythrocyte fragmentation and organ injury in mice. GO:0070948 instead regulates directed killing of a target cell by a neutrophil. The transferred annotation overstates that process relative to the demonstrated clearance mechanism. The positive NET-degradation result is retained; neither inaccessible supplementary methods nor human clinical observations are recast as a target-killing assay. Supporting Evidence: |
| GO:0070948 regulation of neutrophil mediated cytotoxicity | ISS PMID:29191910 Host DNases prevent vascular occlusion by neutrophil extrace... | MARK AS OVER ANNOTATED | Summary: NET-clot clearance does not establish directed neutrophil target-cell killing. Reason: PMID:29191910 shows extracellular DNA digestion and protection from vascular obstruction, erythrocyte fragmentation and organ injury in mice. GO:0070948 instead regulates directed killing of a target cell by a neutrophil. The transferred annotation overstates that process relative to the demonstrated clearance mechanism. The positive NET-degradation result is retained; neither inaccessible supplementary methods nor human clinical observations are recast as a target-killing assay. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which cell types use an intracellular DNASE1L3 pool versus entry of secreted enzyme for nuclear fragmentation during membrane injury, and how does PARP-dependent inhibition control each context?
Q: Does the 275-residue natural product retain secretion, catalytic activity and access to nucleosomal or membrane-associated DNA?
Q: Can host-mediated NET disassembly be represented distinctly from NET formation and symbiont-mediated trap disruption, without conflating clearance with neutrophil activation or directed cytotoxicity?
Q: Does DNASE1L3 cleave cell-surface DNA while it is still bound to heparan sulfate proteoglycans and surface proteins, or only after release, and does the C-terminal peptide that aids access to membrane-associated chromatin also govern this activity?
Q: Is the DNA that DNASE1L3 removes from primary B cells mitochondrial, as in the cell lines, and does its accumulation in DNASE1L3-deficient people feed the anti-dsDNA response?
Q: Should GO add an extracellular DNA catabolic process term (see proposed_new_terms), so that breakdown of plasma, microparticle, NET and cell-surface DNA by DNASE1L3 and DNASE1 can be distinguished from intracellular DNA degradation?
Experiment: Compare sequence-verified natural 305- and 275-residue products in matched secretion and substrate-cleavage assays, controlling protein amount and testing naked, nucleosomal and microparticle-associated DNA.
Experiment: Measure endogenous DNASE1L3 redistribution and DNA fragmentation with time-resolved caspase, membrane-integrity and CAD controls to distinguish apoptosis from secondary necrosis.
Experiment: Sequence the surface DNA released from primary B cells of Dnase1l3-/- and wild-type mice, and of R206C and reference-allele human donors, to test whether the extra surface DNA is mitochondrial; include wild-type versus C-terminal-truncated recombinant enzyme and heparinase treatment to test how proteoglycan tethering and the C-terminal peptide govern access.
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