id: MODULE:nucleotide_excision_repair title: Mammalian nucleotide excision repair — GG-NER (XPC-RAD23B-CETN2, UV-DDB/CRL4-DDB2) and TC-NER (stalled RNA Pol II, CSB, CRL4-CSA, UVSSA, ELOF1) damage recognition, TFIIH opening, XPA-RPA verification, XPF-ERCC1 and XPG dual incision, PCNA/RFC-dependent repair synthesis by Pol delta, epsilon or kappa, and ligation by LIG1 or LIG3-XRCC1 description: >- Nucleotide excision repair (NER) removes a wide range of structurally unrelated, helix-distorting DNA lesions, most prominently the UV photoproducts (cyclobutane pyrimidine dimers and 6-4 photoproducts) and bulky chemical adducts, by excising a 24-32 nucleotide single-stranded oligonucleotide containing the lesion and resynthesising the gap. Mammalian NER has two damage-recognition sub-pathways that converge on a common core. In global genome NER (GG-NER), the XPC-RAD23B-centrin 2 complex detects the unpaired bases opposite a lesion anywhere in the genome; for CPDs, which distort the helix only slightly, the UV-DDB complex (DDB2 within the DDB1-CUL4-RBX1 ubiquitin ligase) binds the lesion first, ubiquitylates XPC, histones and itself, and hands the lesion over to XPC. In transcription-coupled NER (TC-NER), RNA polymerase II stalled at a lesion in the transcribed strand is the sensor: CSB (ERCC6), a SWI2/SNF2-family DNA translocase, binds the arrested polymerase and recruits the CSA (ERCC8) substrate receptor of a second DDB1-CUL4-RBX1 ligase (CRL4-CSA); CSA brings UVSSA, and ELOF1 positions UVSSA and CRL4-CSA so that RPB1 is ubiquitylated on Lys1268. Both sub-pathways then recruit the ten-subunit transcription factor TFIIH, in GG-NER through XPC and in TC-NER through UVSSA. The XPB (ERCC3) ATPase anchors TFIIH and opens the DNA, and the XPD (ERCC2) 5'-3' helicase extends the bubble to about 30 nucleotides and scans the strand to verify the lesion; the CDK-activating kinase subcomplex leaves TFIIH during this step. XPA and the single-stranded DNA-binding protein RPA bind the opened intermediate, verify the damaged strand and position the two structure-specific endonucleases: XPF-ERCC1 incises 5' to the lesion and XPG incises 3' to it. The 5' incision lets RFC load PCNA, and DNA polymerase delta, epsilon or kappa fills the gap; the 3' incision by XPG then releases the excised oligonucleotide. DNA ligase I or the DNA ligase III-XRCC1 complex seals the remaining nick. Inherited defects in NER proteins cause xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy and UV-sensitive syndrome. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000130 title: nucleotide excision repair pathway statement: >- The module boundary follows the RGD Pathway Ontology term and its diagram. The diagram groups GG-NER recognition (Xpc with Rad23b and Cetn2; Ddb1-Ddb2), TC-NER recognition (Ercc6 with the stalled polrII complex and Ercc8; Ercc8 with Gtf2h2, Hmgn1 and Xab2), the TFIIH complex and helix unwinding (Ercc3 and Gtf2h1 associated with Xpc), DNA incision (Ercc1-Ercc4 and Ercc5 with the Rpa complex; Ercc1 with Xpa), and repair synthesis and ligation (Pcna with the Rfc complex, the pold and pole complexes and Polk; Lig3 with Xrcc1; Lig1). Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000130.yaml). - source_id: GO:0006289 title: nucleotide-excision repair statement: >- The GO process mapped to PW:0000130 (skos:closeMatch, from the PW definition cross-reference and a label match in projects/RGD_PATHWAY_ONTOLOGY/data/module_seeds.yaml). It is the module's process concept. - source_id: GO:0070911 title: global genome nucleotide-excision repair statement: Process concept of the GG-NER recognition variant. - source_id: GO:0006283 title: transcription-coupled nucleotide-excision repair statement: Process concept of the TC-NER recognition variant. - source_id: PMID:7697716 title: Mammalian DNA nucleotide excision repair reconstituted with purified protein components. statement: >- Defines the core of the module: the incision reaction and complete repair synthesis were reconstituted from purified factors, and UV-DDB was stimulatory but not essential in vitro. supporting_text: The incision reaction was then reconstituted with the purified proteins RPA, XPA, TFIIH (containing XPB and XPD), XPC, UV-DDB, XPG, partially purified ERCC1/XPF complex, and a factor designated IF7. - source_id: PMID:9734359 title: Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. statement: >- Two-step model: subpathway-specific lesion detection (XPC in GG-NER, stalled RNA polymerase II in TC-NER) followed by common verification. supporting_text: In analogy, in the transcription-coupled NER subpathway, RNA polymerase II may take the role of XPC. notes: >- Derived from the RGD Pathway Ontology diagram PW:0000130 (nucleotide excision repair pathway) through the RGD_PATHWAY_ONTOLOGY project's diagram->module route (seed in projects/RGD_PATHWAY_ONTOLOGY/data/module_seeds.yaml, tier related_module_only because the GO term is shared with the prokaryotic module). RGD curates 39 human genes to PW:0000130: CETN2 DDB1 DDB2 ERCC1 ERCC2 ERCC3 ERCC4 ERCC5 ERCC6 ERCC8 GTF2H1 GTF2H2 HMGN1 LIG1 LIG3 PCNA POLD1 POLD2 POLD3 POLD4 POLE POLE2 POLE3 POLE4 POLK RAD23B RFC1 RFC2 RFC3 RFC4 RFC5 RPA1 RPA2 RPA3 RPA4 XAB2 XPA XPC XRCC1. Thirty-six are modelled as participants; HMGN1, XAB2 and RPA4 are not (decision 6). Nine gene products not on the RGD list are added because the steps RGD draws cannot be stated without them: the remaining TFIIH core subunits GTF2H3, GTF2H4 and GTF2H5 (RGD draws "TFIIH complex" but lists only Gtf2h1 and Gtf2h2), the cullin and RING subunits CUL4A, CUL4B and RBX1 of the two CRL4 ligases (RGD draws Ddb1-Ddb2 and Ercc8 without the ligase core), and, for TC-NER, the stalled RNA polymerase II (represented by POLR2A), UVSSA and ELOF1, which the human TC-NER GO-CAM models. Molecular functions were taken from each protein's experimental GO annotations in QuickGO (November 2026) and, where a gene review exists (DDB1, DDB2, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, ERCC8, CUL4B, RBX1, POLD2, POLE4), from its core functions: XPB is typed DNA translocase activity and CSB DNA translocase activity as in their reviews, and XPF-ERCC1 ds/ssDNA junction-specific dsDNA endonuclease activity as in the ERCC4 review. Deliberate departures: PCNA carries DNA polymerase processivity factor activity, which has no experimental human GOA row; LIG1 is typed DNA ligase (ATP) activity, the child of its experimental DNA ligase activity; RNA polymerase II carries its transcription activity, not the GO:0140612 DNA damage sensor activity used for XPC. That term describes a molecule that recognises a DNA structure and initiates a response, as XPC does by binding the helix distortion. The polymerase recognises nothing: it detects the lesion only by stalling while it transcribes, and no human GOA row puts GO:0140612 on RNA polymerase II. Subunits with no experimental molecular function relevant to NER (RAD23B, CETN2, GTF2H1-5, RPA3, RFC1-5, POLD2-4, POLE2-4, XRCC1) are units without a function; their roles are given in prose. RAD23B has an IDA row for DNA damage sensor activity (PMID:19941824), which is the activity of the XPC complex and is recorded on XPC and on the complex annoton. UniProt labels follow the current recommended names (UniProt release 2026_04, 4 November 2026), including the recent "Lysine-specific demethylase RAD23B" for P54727, the UV excision repair protein RAD23 homolog B. Boundary decisions. (1) Sub-pathways as a ROUTE variant set. GG-NER and TC-NER differ only in lesion recognition and TFIIH recruitment, so they are two variants of part 1 (selection ONE_OR_MORE, since both operate in the same cell); everything from TFIIH onward is shared core. In GG-NER, UV-DDB is modelled as an annoton within the GG-NER variant rather than as a separate required step because it is dispensable in the reconstituted reaction (PMID:7697716) though needed in cells for CPD repair. (2) TFIIH is one complex annoton whose active units are the seven core subunits. Only XPB and XPD carry functions (DNA translocase and 5'-3' helicase); p62, p44, p52, p34 and p8 are units without a GO function, with their NER roles (XPC/UVSSA binding, XPD and XPB stimulation, stabilisation) in prose. The CDK-activating kinase subcomplex (CDK7, CCNH, MNAT1), which completes the ten-subunit holo-TFIIH that RGD describes, is excluded: it is released from TFIIH during NER and its kinase is a transcription activity; RGD does not list it either. (3) Repair synthesis is modelled here rather than referenced. modules/ was searched for human DNA replication, PCNA, RFC, clamp loader, polymerase and ligase modules: the only related modules are other-taxon ones (dmel_dna_polymerase_complexes, dmel_elg1_rfc_like_complex, dmel_9_1_1_checkpoint_clamp, bacterial_chromosomal_dna_replication), so there is nothing human to module_ref. The repair-synthesis and ligation parts are kept to the proteins RGD draws (PCNA, RFC, Pol delta, Pol epsilon, Pol kappa, LIG1, LIG3-XRCC1); when a human replisome or Okazaki-fragment module exists, the Pol delta, Pol epsilon, RFC and PCNA annotons should become module_refs. CTF18-RFC (CHTF18-DSCC1-CTF8 with RFC2-5), which loads PCNA for Pol epsilon in NER (PMID:20227374), and RAD18-dependent PCNA monoubiquitination for Pol kappa are named here but not modelled. (4) RPA is the canonical RPA1-RPA2-RPA3 trimer. RPA4, the RPA2 paralogue of the alternative RPA, is on the RGD list but there is no cached evidence for its participation in NER, so it is excluded. (5) GO's NER incision terms (5'- and 3'-to-lesion, and the parent DNA incision term) are obsolete, so the dual-incision node has no process concept and its annotons carry nucleotide-excision repair. (6) HMGN1 and XAB2 are excluded. RGD draws both associated with Ercc8. HMGN1 is a nucleosome-binding chromatin-unfolding protein recruited in TC-NER through CSA, and XAB2 is a core spliceosomal (Prp19-associated) protein that binds XPA, CSA and CSB; neither has an experimental molecular function in human GOA that would place it as a performer of an NER step, and neither is in the human TC-NER GO-CAM, so both are left as candidate accessory factors. The diagram's link to PW:0001337 (chromatin modification/remodeling pathway) likewise covers the "access-repair-restore" chromatin context, which is out of scope; so are the deubiquitinases USP7 (via UVSSA) and USP44/USP24 (stabilising DDB2), PARP1/PARP2 recruitment to DDB2, and the post-repair restart of transcription. (7) Substrate versus participant: RNA polymerase II is a participant, not merely the ubiquitylation substrate of CRL4-CSA, because its own translocation detects the lesion and the arrested complex is the platform the TC-NER factors assemble on (the stalled polymerase is the sensor in RGD's diagram and in PMID:9734359). XPC is ubiquitylated by UV-DDB but is likewise a participant through its own sensor activity. (8) The prokaryotic analogue is modules/bacterial_nucleotide_excision_repair (UvrA-UvrB-UvrC with Mfd for transcription coupling). The two systems share the logic of recognition, verification by a helicase, dual incision and resynthesis but no homologous core proteins, so it is not referenced as a module_ref. GO-CAM links. gomodel:6796b94c00002938 (TC-NER by ERCC6, ERCC8, ELOF1 and UVSSA) grounds the TC-NER variant activity by activity. gomodel:6348a65d00002206 (USP44 stabilisation of DDB2) grounds the DDB2 and XPC annotons; its USP44 activity is not modelled here. The seed's best_gocam is this USP44 model (overlap 2), and it is relevant. In gomodel:617b481400000521 (KAT5 acetylation of XPF) the XPF activities are enabled by the non-displayed isoform Q92889-2 rather than the canonical sequence; the module links only the endonuclease activity. Observations for upstream review: in gomodel:6796b94c00002938 CSB is typed chromatin-protein adaptor activity whereas its gene review's core activity is DNA translocase activity, and UVSSA is typed RNA polymerase inhibitor activity rather than the TFIIH-recruiting chromatin-protein adaptor activity that carries its IDA in human GOA (PMID:32355176); the KAT5 model's isoform-level enabled_by for XPF may be unintended. PANTHER family ids and PTNs are deliberately not asserted. module: id: nucleotide_excision_repair label: Mammalian nucleotide excision repair module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: nucleotide-excision repair term: id: GO:0006289 label: nucleotide-excision repair description: >- The GO process mapped to PW:0000130; both sub-pathways and the shared core. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cellular_components: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage parts: - order: 1 role: lesion recognition by one of two sub-pathways node: id: damage_recognition label: NER damage recognition (GG-NER or TC-NER) module_type: BIOLOGICAL_PROCESS description: >- The two sub-pathways differ only in how the lesion is first detected and how TFIIH is brought to it. Both may act in the same cell: TC-NER on the transcribed strand of active genes, GG-NER everywhere else. concepts: - preferred_term: nucleotide-excision repair, DNA damage recognition term: id: GO:0000715 label: nucleotide-excision repair, DNA damage recognition variant_sets: - id: ner_subpathway label: NER damage-recognition sub-pathway axis: genomic context of the lesion (anywhere in the genome versus the transcribed strand of an active gene) variant_kind: ROUTE selection: ONE_OR_MORE variants: - id: gg_ner_recognition label: Global genome NER recognition by XPC-RAD23B-CETN2, assisted by UV-DDB module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: global genome nucleotide-excision repair term: id: GO:0070911 label: global genome nucleotide-excision repair annotons: - id: uv_ddb_crl4 label: UV-DDB (CRL4-DDB2) binds the lesion and ubiquitylates XPC participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: UV-DDB / CRL4-DDB2 (DDB1-DDB2-CUL4-RBX1) term: id: GO:0080008 label: Cul4-RING E3 ubiquitin ligase complex active_units: - id: uvddb_ddb2 label: DDB2 lesion-binding substrate receptor role: Binds CPDs and 6-4 photoproducts in nucleosomal DNA; the damage-recognition subunit (XPE). participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DDB2 term: id: UniProtKB:Q92466 label: DNA damage-binding protein 2 function: preferred_term: damaged DNA binding term: id: GO:0003684 label: damaged DNA binding - id: uvddb_ddb1 label: DDB1 adaptor role: Links DDB2 to the cullin scaffold. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DDB1 term: id: UniProtKB:Q16531 label: DNA damage-binding protein 1 function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity - id: uvddb_cul4 label: CUL4A or CUL4B scaffold role: Cullin scaffold; CUL4A and CUL4B are interchangeable paralogues in this ligase. participant: selector_type: FAMILY family: preferred_term: cullin 4 paralogues (CUL4A, CUL4B) representative_members: - preferred_term: CUL4A term: id: UniProtKB:Q13619 label: Cullin-4A - preferred_term: CUL4B term: id: UniProtKB:Q13620 label: Cullin-4B function: preferred_term: ubiquitin ligase complex scaffold activity term: id: GO:0160072 label: ubiquitin ligase complex scaffold activity - id: uvddb_rbx1 label: RBX1 RING subunit role: RING subunit that binds the ubiquitin-charged E2. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RBX1 term: id: UniProtKB:P62877 label: E3 ubiquitin-protein ligase RBX1 function: preferred_term: ubiquitin protein ligase activity term: id: GO:0061630 label: ubiquitin protein ligase activity function: preferred_term: ubiquitin protein ligase activity term: id: GO:0061630 label: ubiquitin protein ligase activity targets: - preferred_term: XPC term: id: UniProtKB:Q01831 label: DNA repair protein complementing XP-C cells - preferred_term: DDB2 (autoubiquitylation) term: id: UniProtKB:Q92466 label: DNA damage-binding protein 2 processes: - preferred_term: global genome nucleotide-excision repair term: id: GO:0070911 label: global genome nucleotide-excision repair locations: - preferred_term: chromatin term: id: GO:0000785 label: chromatin role_description: >- Optional accelerator of GG-NER, essential in cells for efficient repair of CPDs but dispensable for the reconstituted reaction. DDB2 binding and the ligase's ubiquitylation of XPC, of DDB2 itself and of histones transfer the lesion from UV-DDB to XPC and promote DDB2 degradation. evidence: - source_id: PMID:15882621 statement: UV-DDB-CRL4 polyubiquitylates XPC and DDB2, which transfers the lesion to XPC. supporting_text: Our results strongly suggest that ubiquitylation plays a critical role in the transfer of the UV-induced lesion from UV-DDB to XPC. - source_id: PMID:12732143 statement: DDB2 and CSA each form a DDB1-CUL4A-RBX1 (Roc1) ubiquitin ligase. supporting_text: Here, we show that DDB2 and CSA are each integrated into nearly identical complexes via interaction with DDB1. Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity. gocam_associations: - model: gomodel:6348a65d00002206 activity: gomodel:6348a65d00002206/6348a65d00002216 title: DDB2 damaged DNA binding (GO:0003684), USP44-mediated stabilization of DDB2 to Facilitate Nucleotide Excision Repair (Human) - id: xpc_complex_sensor label: XPC-RAD23B-CETN2 detects the helix distortion participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: XPC complex (XPC-RAD23B-CETN2) term: id: GO:0071942 label: XPC complex active_units: - id: xpc_xpc label: XPC damage sensor role: Binds the unpaired bases opposite the lesion and recruits TFIIH through XPB and p62. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: XPC term: id: UniProtKB:Q01831 label: DNA repair protein complementing XP-C cells function: preferred_term: DNA damage sensor activity term: id: GO:0140612 label: DNA damage sensor activity - id: xpc_rad23b label: RAD23B (HR23B) stabilising subunit role: Stabilises XPC and stimulates its damage binding; RAD23A can substitute. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RAD23B term: id: UniProtKB:P54727 label: Lysine-specific demethylase RAD23B - id: xpc_cetn2 label: Centrin 2 (CETN2) role: Binds the XPC C-terminal helix and enhances XPC damage binding and GG-NER. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CETN2 term: id: UniProtKB:P41208 label: Centrin-2 function: preferred_term: DNA damage sensor activity term: id: GO:0140612 label: DNA damage sensor activity processes: - preferred_term: global genome nucleotide-excision repair term: id: GO:0070911 label: global genome nucleotide-excision repair locations: - preferred_term: chromatin term: id: GO:0000785 label: chromatin role_description: >- The initiating GG-NER sensor. XPC recognises the distortion rather than the damaged base itself, binding the undamaged strand with a directional orientation that selects the strand later scanned by TFIIH-XPD; it then recruits TFIIH. evidence: - source_id: PMID:9734359 statement: XPC-HR23B is the earliest GG-NER damage detector and acts before XPA. supporting_text: 'Using a novel DNA damage recognition-competition assay, we identified XPC-HR23B as the earliest damage detector to initiate NER: it acts before the known damage-binding protein XPA.' - source_id: PMID:12509299 statement: XPC-HR23B prefers single-strand/double-strand junctions, i.e. unpaired bases. supporting_text: Although XPC-HR23B showed significantly higher affinity for single-stranded DNA than double-stranded DNA, specific secondary structures of DNA, involving a single- and double-strand junction, were strongly preferred by the complex. - source_id: PMID:15964821 statement: Centrin 2 enhances XPC damage binding and NER dual incision. supporting_text: Furthermore, centrin 2 enhanced the cell-free NER dual incision and damaged DNA binding activities of XPC, which likely require physical interaction between XPC and centrin 2. - source_id: PMID:10734143 statement: XPC-HR23B recruits TFIIH to damaged DNA. supporting_text: We conclude that the XPC-HR23B protein complex plays a crucial role in the recruitment of TFIIH to damaged DNA in global genome repair. gocam_associations: - model: gomodel:6348a65d00002206 activity: gomodel:6348a65d00002206/6348a65d00002224 title: XPC DNA damage sensor activity (GO:0140612), USP44-mediated stabilization of DDB2 to Facilitate Nucleotide Excision Repair (Human) - id: tc_ner_recognition label: Transcription-coupled NER recognition at stalled RNA polymerase II by CSB, CRL4-CSA, UVSSA and ELOF1 module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: transcription-coupled nucleotide-excision repair term: id: GO:0006283 label: transcription-coupled nucleotide-excision repair annotons: - id: stalled_rnapii label: Elongating RNA polymerase II stalled at a template-strand lesion participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: RNA polymerase II elongation complex term: id: GO:0005665 label: RNA polymerase II, core complex active_units: - id: rnapii_rpb1 label: RPB1 (POLR2A) catalytic subunit role: Catalytic subunit; its Lys1268 is ubiquitylated by CRL4-CSA during TC-NER. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: POLR2A term: id: UniProtKB:P24928 label: DNA-directed RNA polymerase II subunit RPB1 function: preferred_term: DNA-directed RNA polymerase activity term: id: GO:0003899 label: DNA-directed RNA polymerase activity function: preferred_term: DNA-directed RNA polymerase activity term: id: GO:0003899 label: DNA-directed RNA polymerase activity processes: - preferred_term: transcription-coupled nucleotide-excision repair term: id: GO:0006283 label: transcription-coupled nucleotide-excision repair locations: - preferred_term: chromatin term: id: GO:0000785 label: chromatin role_description: >- The TC-NER damage sensor. Translocation of the elongating polymerase along the template is what detects the lesion; the arrested enzyme is then the platform on which CSB, CRL4-CSA, UVSSA and ELOF1 assemble and the ubiquitylation target that licenses TFIIH recruitment. Its transcription activity is recorded as the function, not GO:0140612 DNA damage sensor activity: the polymerase detects the lesion only by stalling during transcription rather than by recognising the distortion as XPC does, and no human GOA row assigns it that term. evidence: - source_id: PMID:34526721 statement: Pol II stalled at a lesion recruits CSB, CRL4-CSA and UVSSA. supporting_text: Transcription-coupled DNA repair begins when RNA polymerase II (Pol II) stalls at a DNA lesion and recruits the Cockayne syndrome protein CSB, the E3 ubiquitin ligase, CRL4CSA and UV-stimulated scaffold protein A (UVSSA) - id: csb_translocase label: CSB (ERCC6) binds stalled Pol II and recruits CSA participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ERCC6 (CSB) term: id: UniProtKB:Q03468 label: DNA excision repair protein ERCC-6 function: preferred_term: DNA translocase activity term: id: GO:0015616 label: DNA translocase activity processes: - preferred_term: transcription-coupled nucleotide-excision repair term: id: GO:0006283 label: transcription-coupled nucleotide-excision repair locations: - preferred_term: chromatin term: id: GO:0000785 label: chromatin role_description: >- SWI2/SNF2-family ATPase that replaces DSIF on the arrested polymerase, pulls upstream DNA to push Pol II forward over small obstacles, and when the lesion cannot be bypassed recruits CSA through its CSA-interaction motif. Its chromatin-protein adaptor role is the typing used in the TC-NER GO-CAM. evidence: - source_id: PMID:34526721 statement: CSB is a CSA-stimulated translocase acting on upstream DNA. supporting_text: uses the CSA-stimulated translocase activity of CSB to pull on upstream DNA and push Pol II forward - source_id: PMID:32355176 statement: TC-NER is initiated by Pol II-bound CSB, which recruits CSA. supporting_text: We show that TCR is initiated by RNAPIIo-bound CSB, which recruits CSA through a newly identified CSA-interaction motif (CIM). gocam_associations: - model: gomodel:6796b94c00002938 activity: gomodel:6796b94c00002938/6796b94c00002939 title: ERCC6 chromatin-protein adaptor activity (GO:0140463), Transcription-coupled nucleotide-excision repair by ERRC6, ERCC8, ELOF1 and UVSSA (Human) - id: crl4_csa label: CRL4-CSA ubiquitylates RPB1 and CSB participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: CRL4-CSA (ERCC8-DDB1-CUL4A-RBX1) term: id: GO:0080008 label: Cul4-RING E3 ubiquitin ligase complex active_units: - id: csa_ercc8 label: CSA (ERCC8) WD40 substrate receptor role: Substrate receptor; recruited by CSB and recruits UVSSA. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ERCC8 (CSA) term: id: UniProtKB:Q13216 label: DNA excision repair protein ERCC-8 function: preferred_term: ubiquitin-like ligase-substrate adaptor activity term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity - id: csa_ddb1 label: DDB1 adaptor role: Links CSA to the cullin scaffold. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DDB1 term: id: UniProtKB:Q16531 label: DNA damage-binding protein 1 function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity - id: csa_cul4a label: CUL4A scaffold role: Cullin scaffold of the CSA complex. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CUL4A term: id: UniProtKB:Q13619 label: Cullin-4A function: preferred_term: ubiquitin ligase complex scaffold activity term: id: GO:0160072 label: ubiquitin ligase complex scaffold activity - id: csa_rbx1 label: RBX1 RING subunit role: RING subunit carrying the ligase activity. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RBX1 term: id: UniProtKB:P62877 label: E3 ubiquitin-protein ligase RBX1 function: preferred_term: ubiquitin protein ligase activity term: id: GO:0061630 label: ubiquitin protein ligase activity function: preferred_term: ubiquitin protein ligase activity term: id: GO:0061630 label: ubiquitin protein ligase activity targets: - preferred_term: RPB1 (POLR2A) Lys1268 term: id: UniProtKB:P24928 label: DNA-directed RNA polymerase II subunit RPB1 - preferred_term: CSB (ERCC6) term: id: UniProtKB:Q03468 label: DNA excision repair protein ERCC-6 processes: - preferred_term: transcription-coupled nucleotide-excision repair term: id: GO:0006283 label: transcription-coupled nucleotide-excision repair locations: - preferred_term: chromatin term: id: GO:0000785 label: chromatin role_description: >- Spans the Pol II clamp and ubiquitylates RPB1 Lys1268, which enables TFIIH recruitment to UVSSA; later ubiquitylation of CSB releases the TC-NER factors. evidence: - source_id: PMID:34526721 statement: CRL4-CSA ubiquitylates RPB1 K1268, enabling TFIIH recruitment to UVSSA. supporting_text: If the lesion cannot be bypassed, CRL4CSA spans over the Pol II clamp and ubiquitylates the RPB1 residue K1268, enabling recruitment of TFIIH to UVSSA and DNA repair. - source_id: PMID:12732143 statement: CSA is the substrate receptor of a DDB1-CUL4A-RBX1 ligase. supporting_text: Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity. gocam_associations: - model: gomodel:6796b94c00002938 activity: gomodel:6796b94c00002938/6796b94c00002950 title: ERCC8 ubiquitin-like ligase-substrate adaptor activity (GO:1990756) - model: gomodel:6796b94c00002938 activity: gomodel:6796b94c00002938/6796b94c00002962 title: RBX1 ubiquitin protein ligase activity (GO:0061630) - id: uvssa_tfiih_recruitment label: UVSSA recruits TFIIH to the arrested polymerase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: UVSSA term: id: UniProtKB:Q2YD98 label: UV-stimulated scaffold protein A function: preferred_term: chromatin-protein adaptor activity term: id: GO:0140463 label: chromatin-protein adaptor activity processes: - preferred_term: transcription-coupled nucleotide-excision repair term: id: GO:0006283 label: transcription-coupled nucleotide-excision repair locations: - preferred_term: chromatin term: id: GO:0000785 label: chromatin role_description: >- The TC-NER counterpart of XPC: it binds stalled Pol II after CSA and is the factor that recruits TFIIH. A TFIIS-like element of UVSSA also blocks TFIIS-mediated reactivation of the polymerase (the RNA polymerase inhibitor activity used in the GO-CAM), and UVSSA brings the deubiquitinase USP7, which stabilises CSB. evidence: - source_id: PMID:32355176 statement: UVSSA is the key TFIIH-recruiting factor in TC-NER. supporting_text: Importantly, we find that UVSSA is the key factor that recruits the TFIIH complex in a manner that is stimulated by CSB and CSA. - source_id: PMID:38316879 statement: A TFIIS-like element of UVSSA prevents reactivation of Pol II. supporting_text: a transcription factor IIS (TFIIS)-like element in UVSSA gets ordered and extends through the Pol II pore, thus preventing reactivation of Pol II by TFIIS - source_id: PMID:22466611 statement: UVSSA delivers USP7 to TC-NER complexes and stabilises CSB. supporting_text: implicated in stabilizing the TC-NER master organizing protein ERCC6 (also known as CSB) by delivering the deubiquitinating enzyme USP7 to TC-NER complexes gocam_associations: - model: gomodel:6796b94c00002938 activity: gomodel:6796b94c00002938/6796b94c00002974 title: UVSSA RNA polymerase inhibitor activity (GO:0140870) - id: elof1_adaptor label: ELOF1 positions UVSSA and CRL4-CSA on arrested Pol II participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ELOF1 term: id: UniProtKB:P60002 label: Transcription elongation factor 1 homolog function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity processes: - preferred_term: transcription-coupled nucleotide-excision repair term: id: GO:0006283 label: transcription-coupled nucleotide-excision repair locations: - preferred_term: chromatin term: id: GO:0000785 label: chromatin role_description: >- Elongation factor bound to Pol II that stably positions UVSSA and CRL4-CSA, promoting ligase neddylation and RPB1 ubiquitylation. Not on the RGD list (identified as a TC-NER factor in 2021); included because the human TC-NER GO-CAM models it. evidence: - source_id: PMID:38316879 statement: ELOF1 is an adaptor that positions UVSSA and CRL4-CSA on arrested Pol II. supporting_text: we found that ELOF1 serves as an adaptor to stably position UVSSA and CRL4CSA on arrested Pol II, leading to ligase neddylation and activation of Pol II ubiquitylation gocam_associations: - model: gomodel:6796b94c00002938 activity: gomodel:6796b94c00002938/6796b94c00002982 title: ELOF1 protein-macromolecule adaptor activity (GO:0030674) connections: - source: stalled_rnapii target: csb_translocase connection_type: PROVIDES_INPUT_FOR description: The arrested polymerase is the binding platform for CSB. - source: csb_translocase target: crl4_csa connection_type: POSITIVELY_REGULATES description: CSB recruits CSA through its CSA-interaction motif. - source: crl4_csa target: uvssa_tfiih_recruitment connection_type: POSITIVELY_REGULATES description: CSA facilitates UVSSA association with stalled Pol II. - source: elof1_adaptor target: crl4_csa connection_type: POSITIVELY_REGULATES description: ELOF1 positions CRL4-CSA and UVSSA and activates RPB1 ubiquitylation. notes: >- ROUTE variants: the two sub-pathways use different proteins and different activities to reach the same intermediate (a lesion with TFIIH bound). - order: 2 role: TFIIH recruitment, DNA opening and lesion scanning node: id: tfiih_opening label: TFIIH opens the DNA around the lesion and XPD verifies it module_type: BIOLOGICAL_PROCESS description: >- TFIIH is recruited by XPC (GG-NER) or UVSSA (TC-NER). The XPB ATPase, stimulated by p52, anchors the complex and opens the duplex; the XPD helicase, regulated by p44, extends the bubble 5' to 3' and stalls at the lesion, which verifies it. The CAK subcomplex (CDK7, cyclin H, MAT1) is released from TFIIH during NER and is not a part of this step. concepts: - preferred_term: nucleotide-excision repair, preincision complex assembly term: id: GO:0006294 label: nucleotide-excision repair, preincision complex assembly annotons: - id: tfiih_core label: TFIIH core complex unwinds the damaged duplex participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: TFIIH core complex (XPB, XPD, p62, p52, p44, p34, p8) term: id: GO:0000439 label: transcription factor TFIIH core complex active_units: - id: tfiih_xpb label: XPB (ERCC3) ATPase/translocase role: >- Its ATPase activity, not its helicase activity, is needed to anchor TFIIH and open damaged DNA. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ERCC3 (XPB) term: id: UniProtKB:P19447 label: General transcription and DNA repair factor IIH helicase/translocase subunit XPB function: preferred_term: DNA translocase activity term: id: GO:0015616 label: DNA translocase activity - id: tfiih_xpd label: XPD (ERCC2) 5'-3' helicase role: Extends the bubble and scans the damaged strand 5' to 3', stalling at the lesion. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ERCC2 (XPD) term: id: UniProtKB:P18074 label: General transcription and DNA repair factor IIH helicase subunit XPD function: preferred_term: 5'-3' DNA helicase activity term: id: GO:0043139 label: 5'-3' DNA helicase activity - id: tfiih_p62 label: p62 (GTF2H1) role: Binds XPC (and UVSSA) through its PH domain, linking the recognition factors to TFIIH. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GTF2H1 (p62) term: id: UniProtKB:P32780 label: General transcription factor IIH subunit 1 - id: tfiih_p44 label: p44 (GTF2H2) role: Binds and stimulates XPD; also the TFIIH subunit RGD draws associated with CSA. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GTF2H2 (p44) term: id: UniProtKB:Q13888 label: General transcription factor IIH subunit 2 - id: tfiih_p52 label: p52 (GTF2H4) role: Binds XPB and stimulates its ATPase. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GTF2H4 (p52) term: id: UniProtKB:Q92759 label: General transcription factor IIH subunit 4 - id: tfiih_p34 label: p34 (GTF2H3) role: Structural core subunit that partners p44. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GTF2H3 (p34) term: id: UniProtKB:Q13889 label: General transcription factor IIH subunit 3 - id: tfiih_p8 label: p8/TTD-A (GTF2H5) role: Stabilises p52 and TFIIH and is needed for efficient NER; mutated in trichothiodystrophy group A. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GTF2H5 (p8, TTD-A) term: id: UniProtKB:Q6ZYL4 label: General transcription factor IIH subunit 5 function: preferred_term: 5'-3' DNA helicase activity term: id: GO:0043139 label: 5'-3' DNA helicase activity processes: - preferred_term: nucleotide-excision repair, preincision complex assembly term: id: GO:0006294 label: nucleotide-excision repair, preincision complex assembly locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- Common to both sub-pathways and also the basal transcription factor of RNA polymerase II. The complex activity recorded is XPD helicase, which performs the unwinding and lesion verification; XPB contributes ATP-driven opening and anchoring. evidence: - source_id: PMID:17466626 statement: Opening is driven by XPB ATPase (stimulated by p52) with XPD helicase; XPB helicase is dispensable. supporting_text: Our results suggest a mechanism in which the helicase activity of XPB is not used for the opening and repair of damaged DNA, which is instead only driven by its ATPase activity, in combination with the helicase activity of XPD. - source_id: PMID:8413672 statement: XPD is a DNA helicase. supporting_text: We have purified the XPD protein to near homogeneity and show that it possesses single-stranded DNA-dependent ATPase and DNA helicase activities. - source_id: PMID:19941824 statement: Lesion verification involves 5'-to-3' strand scanning, implicating XPD. supporting_text: Translocation by the NER machinery exhibits a 5'-to-3' directionality, strongly suggesting involvement of the XPD helicase, a component of TFIIH. - source_id: PMID:10734143 statement: XPC binds TFIIH through XPB and/or p62. supporting_text: This interaction is thought to be mediated through the specific affinity of XPC for the TFIIH subunits XPB and/or p62, which are essential for both basal transcription and nucleotide excision repair. - order: 3 role: damage verification and pre-incision complex assembly node: id: preincision_verification label: XPA and RPA verify the lesion and assemble the pre-incision complex module_type: BIOLOGICAL_PROCESS description: >- XPA binds the kinked, damaged strand at the 5' junction of the bubble and RPA coats the undamaged strand; together they verify the lesion, release CAK, and orient the two endonucleases (RPA and XPA position XPF-ERCC1 on the 5' side, RPA positions XPG on the 3' side). concepts: - preferred_term: nucleotide-excision repair, preincision complex assembly term: id: GO:0006294 label: nucleotide-excision repair, preincision complex assembly annotons: - id: xpa_verifier label: XPA damaged-DNA binding and verification participant: selector_type: GENE_PRODUCT gene_product: preferred_term: XPA term: id: UniProtKB:P23025 label: DNA repair protein complementing XP-A cells function: preferred_term: damaged DNA binding term: id: GO:0003684 label: damaged DNA binding processes: - preferred_term: nucleotide-excision repair, preincision complex assembly term: id: GO:0006294 label: nucleotide-excision repair, preincision complex assembly locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- Common verifier and organiser of the pre-incision complex; it binds RPA, TFIIH and ERCC1, recruiting XPF-ERCC1. evidence: - source_id: PMID:9734359 statement: XPA acts after XPC as the common damage verifier and adaptor to the NER core. supporting_text: After this subpathway-specific initial lesion detection, XPA may function as a common damage verifier and adaptor to the core of the NER apparatus. - source_id: PMID:7700386 statement: RPA and XPA bind lesions cooperatively. supporting_text: a complex of RPA and XPA showed a striking cooperativity in binding to DNA lesions indicates that RPA may function at the very earliest stage of excision repair - id: rpa_ssdna label: RPA binds the undamaged strand and positions the nucleases participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: RPA heterotrimer (RPA1-RPA2-RPA3) term: id: GO:0005662 label: DNA replication factor A complex active_units: - id: rpa_rpa1 label: RPA1 (RPA70) role: Main single-stranded DNA-binding subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RPA1 term: id: UniProtKB:P27694 label: Replication protein A 70 kDa DNA-binding subunit function: preferred_term: single-stranded DNA binding term: id: GO:0003697 label: single-stranded DNA binding - id: rpa_rpa2 label: RPA2 (RPA32) role: Single-stranded DNA-binding subunit; binds XPA. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RPA2 term: id: UniProtKB:P15927 label: Replication protein A 32 kDa subunit function: preferred_term: single-stranded DNA binding term: id: GO:0003697 label: single-stranded DNA binding - id: rpa_rpa3 label: RPA3 (RPA14) role: Structural subunit of the trimer core. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RPA3 term: id: UniProtKB:P35244 label: Replication protein A 14 kDa subunit function: preferred_term: single-stranded DNA binding term: id: GO:0003697 label: single-stranded DNA binding processes: - preferred_term: nucleotide-excision repair, preincision complex assembly term: id: GO:0006294 label: nucleotide-excision repair, preincision complex assembly locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- Protects the undamaged strand, binds XPA and XPG and stimulates XPF-ERCC1; it stays bound through repair synthesis, where it also interacts with the polymerases. evidence: - source_id: PMID:7700386 statement: RPA binds XPA and XPG and may target XPG to the lesion. supporting_text: In addition, by binding XPG, RPA may target this endonuclease to damaged DNA. - order: 4 role: dual incision node: id: dual_incision label: Dual incision by XPF-ERCC1 (5') and XPG (3') module_type: BIOLOGICAL_PROCESS description: >- XPG is recruited structurally with TFIIH but cuts only after XPF-ERCC1 has incised 5' to the lesion; repair synthesis can begin from the 5' incision before the 3' incision releases the 24-32 nucleotide fragment. GO's three NER incision process terms are obsolete, so this node carries no process concept. annotons: - id: xpf_ercc1_incision label: XPF-ERCC1 incises 5' to the lesion participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: XPF-ERCC1 (ERCC4-ERCC1) endonuclease term: id: GO:0070522 label: ERCC4-ERCC1 complex active_units: - id: xpf_ercc4 label: XPF (ERCC4) nuclease subunit role: Catalytic subunit; cleaves the damaged strand at the 5' ds/ssDNA junction of the bubble. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ERCC4 (XPF) term: id: UniProtKB:Q92889 label: DNA repair endonuclease XPF function: preferred_term: ds/ssDNA junction-specific dsDNA endonuclease activity term: id: GO:0106332 label: ds/ssDNA junction-specific dsDNA endonuclease activity - id: xpf_ercc1 label: ERCC1 non-catalytic subunit role: Non-catalytic partner that binds single-stranded DNA and XPA, recruiting the complex. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ERCC1 term: id: UniProtKB:P07992 label: DNA excision repair protein ERCC-1 function: preferred_term: single-stranded DNA binding term: id: GO:0003697 label: single-stranded DNA binding function: preferred_term: ds/ssDNA junction-specific dsDNA endonuclease activity term: id: GO:0106332 label: ds/ssDNA junction-specific dsDNA endonuclease activity processes: - preferred_term: nucleotide-excision repair term: id: GO:0006289 label: nucleotide-excision repair locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- The 5' incision; the same complex acts in interstrand-crosslink repair and single-strand annealing, which are outside this module. evidence: - source_id: PMID:7559382 statement: Purified XPF-ERCC1 complements NER-defective extracts and cuts bubble DNA. supporting_text: 'The XPF/ERCC4-ERCC1 complex has an endonuclease activity with preference for single-stranded DNA and a single-stranded region of duplex DNA with a "bubble" structure.' gocam_associations: - model: gomodel:617b481400000521 activity: gomodel:617b481400000521/617b481400000536 title: ERCC4 single-stranded DNA endonuclease activity (GO:0000014), KAT5 involvement in nucleotide excision repair (Human) - id: xpg_incision label: XPG incises 3' to the lesion participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ERCC5 (XPG) term: id: UniProtKB:P28715 label: DNA excision repair protein ERCC-5 function: preferred_term: DNA endonuclease activity term: id: GO:0004520 label: DNA endonuclease activity processes: - preferred_term: nucleotide-excision repair term: id: GO:0006289 label: nucleotide-excision repair locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- Structure-specific endonuclease that also stabilises the pre-incision complex and stimulates assembly of the repair-synthesis machinery. evidence: - source_id: PMID:8090225 statement: XPG makes the 3' incision. supporting_text: These data show that XPG has a direct role in making one of the incisions required to excise a damaged oligonucleotide, by cleaving 3' to DNA damage during nucleotide excision repair. - order: 5 role: gap-filling repair synthesis node: id: repair_synthesis label: PCNA/RFC-dependent repair synthesis by Pol delta, Pol epsilon or Pol kappa module_type: BIOLOGICAL_PROCESS description: >- After the 5' incision, RFC loads PCNA at the free 3'-OH and one of three polymerases fills the ~30-nucleotide gap: Pol delta (recruited by RFC1-RFC, the p66 subunit POLD3 and unmodified PCNA) together with Pol kappa (recruited by ubiquitinated PCNA and XRCC1) for about half of the synthesis, and Pol epsilon (recruited by the alternative clamp loader CTF18-RFC) for the rest, mainly in proliferating cells. concepts: - preferred_term: nucleotide-excision repair, DNA gap filling term: id: GO:0006297 label: nucleotide-excision repair, DNA gap filling annotons: - id: rfc_clamp_loader label: RFC loads PCNA at the incised strand participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: replication factor C (RFC1-RFC5) term: id: GO:0005663 label: DNA replication factor C complex active_units: - id: rfc_rfc1 label: RFC1 large subunit role: Large subunit that distinguishes the canonical clamp loader. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RFC1 term: id: UniProtKB:P35251 label: Replication factor C subunit 1 - id: rfc_rfc2 label: RFC2 role: AAA+ small subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RFC2 term: id: UniProtKB:P35250 label: Replication factor C subunit 2 - id: rfc_rfc3 label: RFC3 role: AAA+ small subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RFC3 term: id: UniProtKB:P40938 label: Replication factor C subunit 3 - id: rfc_rfc4 label: RFC4 role: AAA+ small subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RFC4 term: id: UniProtKB:P35249 label: Replication factor C subunit 4 - id: rfc_rfc5 label: RFC5 role: AAA+ small subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RFC5 term: id: UniProtKB:P40937 label: Replication factor C subunit 5 function: preferred_term: DNA clamp loader activity term: id: GO:0003689 label: DNA clamp loader activity targets: - preferred_term: PCNA term: id: UniProtKB:P12004 label: DNA sliding clamp PCNA processes: - preferred_term: nucleotide-excision repair, DNA gap filling term: id: GO:0006297 label: nucleotide-excision repair, DNA gap filling locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- The canonical RFC1-RFC clamp loader is needed for Pol delta recruitment; Pol epsilon instead depends on CTF18-RFC (CHTF18 with RFC2-RFC5), which is not on the RGD list and is recorded in notes. evidence: - source_id: PMID:20227374 statement: RFC1-RFC recruits Pol delta to NER sites; CTF18-RFC recruits Pol epsilon. supporting_text: Pol kappa is recruited to repair sites by ubiquitinated PCNA and XRCC1 and pol delta by the classical replication factor complex RFC1-RFC, together with a polymerase accessory factor, p66, and unmodified PCNA. - id: pcna_clamp label: PCNA sliding clamp tethers the repair polymerases participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PCNA (homotrimer) term: id: UniProtKB:P12004 label: DNA sliding clamp PCNA function: preferred_term: DNA polymerase processivity factor activity term: id: GO:0030337 label: DNA polymerase processivity factor activity processes: - preferred_term: nucleotide-excision repair, DNA gap filling term: id: GO:0006297 label: nucleotide-excision repair, DNA gap filling locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- Homotrimeric clamp; unmodified PCNA recruits Pol delta and monoubiquitinated PCNA recruits Pol kappa. Processivity factor activity has no experimental human GOA row (it is the IBA-level activity of the family). evidence: - source_id: PMID:7697716 statement: Complete repair synthesis was reconstituted with Pol epsilon, RFC, PCNA and DNA ligase I. supporting_text: Complete repair synthesis was achieved by combining these factors with DNA polymerase epsilon, RFC, PCNA, and DNA ligase I. variant_sets: - id: repair_polymerase label: NER repair polymerase axis: DNA polymerase recruited to the gap (proliferation state and recruitment route) variant_kind: REALIZER selection: ONE_OR_MORE variants: - id: pol_delta_variant label: DNA polymerase delta (POLD1-4) module_type: REACTION annotons: - id: pol_delta_synthesis label: Pol delta repair synthesis participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: DNA polymerase delta holoenzyme term: id: GO:0043625 label: delta DNA polymerase complex active_units: - id: pold_pold1 label: POLD1 catalytic subunit role: Polymerase and 3'-5' proofreading exonuclease. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: POLD1 term: id: UniProtKB:P28340 label: DNA polymerase delta catalytic subunit function: preferred_term: DNA-directed DNA polymerase activity term: id: GO:0003887 label: DNA-directed DNA polymerase activity - id: pold_pold2 label: POLD2 B subunit role: Accessory subunit bridging the catalytic subunit to POLD3. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: POLD2 term: id: UniProtKB:P49005 label: DNA polymerase delta subunit 2 - id: pold_pold3 label: POLD3 (p66) PCNA-binding subunit role: Accessory subunit required for Pol delta recruitment to NER sites. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: POLD3 (p66) term: id: UniProtKB:Q15054 label: DNA polymerase delta subunit 3 - id: pold_pold4 label: POLD4 (p12) role: Smallest subunit; degraded after UV damage. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: POLD4 (p12) term: id: UniProtKB:Q9HCU8 label: DNA polymerase delta subunit 4 function: preferred_term: DNA-directed DNA polymerase activity term: id: GO:0003887 label: DNA-directed DNA polymerase activity processes: - preferred_term: nucleotide-excision repair, DNA gap filling term: id: GO:0006297 label: nucleotide-excision repair, DNA gap filling locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage evidence: - source_id: PMID:20227374 statement: About half of NER repair synthesis requires both Pol kappa and Pol delta. supporting_text: We report that, in human fibroblasts, approximately half of the repair synthesis requires both pol kappa and pol delta, and both polymerases can be recovered in the same repair complexes. - id: pol_epsilon_variant label: DNA polymerase epsilon (POLE, POLE2-4) module_type: REACTION annotons: - id: pol_epsilon_synthesis label: Pol epsilon repair synthesis participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: DNA polymerase epsilon holoenzyme term: id: GO:0008622 label: epsilon DNA polymerase complex active_units: - id: pole_pole label: POLE catalytic subunit role: Polymerase and 3'-5' proofreading exonuclease. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: POLE term: id: UniProtKB:Q07864 label: DNA polymerase epsilon catalytic subunit A function: preferred_term: DNA-directed DNA polymerase activity term: id: GO:0003887 label: DNA-directed DNA polymerase activity - id: pole_pole2 label: POLE2 B subunit role: Accessory B subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: POLE2 term: id: UniProtKB:P56282 label: DNA polymerase epsilon subunit 2 - id: pole_pole3 label: POLE3 (p17) role: Histone-fold accessory subunit (also in CHRAC). participant: selector_type: GENE_PRODUCT gene_product: preferred_term: POLE3 term: id: UniProtKB:Q9NRF9 label: DNA polymerase epsilon subunit 3 - id: pole_pole4 label: POLE4 (p12) role: Histone-fold accessory subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: POLE4 term: id: UniProtKB:Q9NR33 label: DNA polymerase epsilon subunit 4 function: preferred_term: DNA-directed DNA polymerase activity term: id: GO:0003887 label: DNA-directed DNA polymerase activity processes: - preferred_term: nucleotide-excision repair, DNA gap filling term: id: GO:0006297 label: nucleotide-excision repair, DNA gap filling locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage evidence: - source_id: PMID:20227374 statement: The rest of NER repair synthesis uses Pol epsilon loaded via CTF18-RFC. supporting_text: The remaining repair synthesis is dependent on pol epsilon, recruitment of which is dependent on the alternative clamp loader CTF18-RFC. - id: pol_kappa_variant label: DNA polymerase kappa (POLK) module_type: REACTION annotons: - id: pol_kappa_synthesis label: Pol kappa repair synthesis participant: selector_type: GENE_PRODUCT gene_product: preferred_term: POLK term: id: UniProtKB:Q9UBT6 label: DNA polymerase kappa function: preferred_term: DNA-directed DNA polymerase activity term: id: GO:0003887 label: DNA-directed DNA polymerase activity processes: - preferred_term: nucleotide-excision repair, DNA gap filling term: id: GO:0006297 label: nucleotide-excision repair, DNA gap filling locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- Y-family polymerase recruited by monoubiquitinated PCNA and XRCC1; works alongside Pol delta. Its translesion-synthesis role is outside this module. evidence: - source_id: PMID:20227374 statement: Pol kappa is recruited by ubiquitinated PCNA and XRCC1. supporting_text: Pol kappa is recruited to repair sites by ubiquitinated PCNA and XRCC1 - order: 6 role: nick ligation node: id: ligation label: Sealing of the repair patch by LIG1 or LIG3-XRCC1 module_type: BIOLOGICAL_PROCESS description: >- The remaining nick is sealed by DNA ligase I, mainly in proliferating cells, or by the DNA ligase III-XRCC1 complex, which acts throughout the cell cycle and is the main NER ligase in quiescent cells. variant_sets: - id: ner_ligase label: NER DNA ligase axis: DNA ligase sealing the repair patch (cell-cycle state) variant_kind: REALIZER selection: ONE_OR_MORE variants: - id: lig1_variant label: DNA ligase I (LIG1) module_type: REACTION annotons: - id: lig1_ligation label: LIG1 seals the NER nick participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LIG1 term: id: UniProtKB:P18858 label: DNA ligase 1 function: preferred_term: DNA ligase (ATP) activity term: id: GO:0003910 label: DNA ligase (ATP) activity processes: - preferred_term: nucleotide-excision repair term: id: GO:0006289 label: nucleotide-excision repair locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage evidence: - source_id: Reactome:R-HSA-5690997 statement: LIG1 and LIG3 both ligate the NER repair patch. supporting_text: Two DNA ligases, LIG1 and LIG3, can perform the ligation in global genome NER (GG-NER), as well as in transcription-coupled NER (TC-NER) - source_id: PMID:7697716 statement: DNA ligase I completes the reconstituted reaction. supporting_text: Complete repair synthesis was achieved by combining these factors with DNA polymerase epsilon, RFC, PCNA, and DNA ligase I. - id: lig3_xrcc1_variant label: DNA ligase III-XRCC1 complex module_type: REACTION annotons: - id: lig3_xrcc1_ligation label: LIG3-XRCC1 seals the NER nick participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: DNA ligase III alpha-XRCC1 complex term: id: GO:0070421 label: DNA ligase III-XRCC1 complex active_units: - id: lig3_lig3 label: LIG3 (ligase III alpha) role: Catalytic ligase subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LIG3 term: id: UniProtKB:P49916 label: DNA ligase 3 function: preferred_term: DNA ligase (ATP) activity term: id: GO:0003910 label: DNA ligase (ATP) activity - id: lig3_xrcc1 label: XRCC1 scaffold role: Non-catalytic scaffold that stabilises LIG3 and also helps recruit Pol kappa. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: XRCC1 term: id: UniProtKB:P18887 label: DNA repair protein XRCC1 function: preferred_term: DNA ligase (ATP) activity term: id: GO:0003910 label: DNA ligase (ATP) activity processes: - preferred_term: nucleotide-excision repair term: id: GO:0006289 label: nucleotide-excision repair locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage evidence: - source_id: Reactome:R-HSA-6782227 statement: LIG1 and LIG3 both ligate the TC-NER repair patch. supporting_text: Two DNA ligases, LIG1 and LIG3, can perform the ligation in transcription-coupled NER (TC-NER), as well as in global genome NER (GG-NER) connections: - source: damage_recognition target: tfiih_opening connection_type: PRECEDES description: XPC (GG-NER) or UVSSA (TC-NER) recruits TFIIH to the lesion. - source: tfiih_opening target: preincision_verification connection_type: PRECEDES description: The opened bubble is bound by XPA and RPA, and XPD stalling verifies the lesion. - source: preincision_verification target: dual_incision connection_type: PRECEDES description: RPA and XPA position XPF-ERCC1 5' and XPG 3' of the lesion. - source: dual_incision target: repair_synthesis connection_type: PRECEDES description: The 5' incision by XPF-ERCC1 provides the 3'-OH primer; synthesis can begin before the 3' incision. - source: repair_synthesis target: ligation connection_type: PRECEDES description: The completed patch leaves a nick that is ligated.