id: PW:0000130 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000130 title: nucleotide excision repair pathway description: DNA lesions, induced by endogenous or exogenous agents, affect the faithful replication of the genome resulting in genetic aberrations that can be deleterious to the cell and organism. Multiple systems have evolved to detect single and double-strand DNA lesions, initiate signals that can be amplified and propagated, and set in motion effectors that can impinge upon DNA repair and checkpoint, various signaling and/or regulatory pathways, as necessary. Together, this vast response mechanism is known as the DNA Damage Response (DDR) pathway whose elements may operate collectively with shared components. The nucleotide excision repair (NER) pathway, is a versatile single-strand DNA repair pathway and part of DDR. It targets various, structurally unrelated DNA modifications that result in distortion of the double helix. NER is subdivided into two sub-pathways that differ in the first step of lesion recognition. The transcription-coupled TC-NER is involved in the repair of lesions within the transcribed strand of active genes whereas the global genome GG-NER is involved in the repair of lesions throughout the genome. The two converge into the core of NER leading to cleavage of the damaged strand on either side of the lesion and excision of a stretch of about 24-32 nucleotides followed by re-synthesis of the missing DNA stretch and ligation. In TC-NER, the stalled RNA polymerase II (PolrII) complex acts as the damage sensor recruiting TC-NER specific factors of which Cackayne syndrome CSA and CSB, the Ercc8 and Ercc6 genes, play essential, but partially understood roles. Ercc6 binds stalled PolrII while Ercc8 interacts with Ercc6, Hmgn1, Xab2 and the Gtf2h2 subunit of TFIIH. Ercc6 has DNA-dependent ATPase activity, recruits histone acetyltransferases and in vitro, has chromatin remodeling activity. In GG-NER, lesions are recognized by Xpc within the Xpc-Rad23b-centrin2 complex and certain types of lesions by the UV-DDB complex (Ddb1-Ddb2-containing E3-ubiquitin ligase complex). The UV-DDB complex is thought to recognize nucleosomes containing the DNA lesion, play a role in chromatin modification. The C-terminus of Xpc interacts with Ercc3 and both termini are used in the interaction with Gtf2h1; the two are subunits of TFIIH. The mammalian TFIIH is a ten subunits complex and a component of the multi-protein pre-initiation complex (PIC) of RNA polymerase II transcription. TFIIH, primarily a Pol II factors, may also be involved in transcription by pol I and III. Ercc3 and another TFIIH subunit, Ercc2, known are XPB and XPD, respectively, are ATP-dependent helicases that open the damaged DNA, melting a region spanning ~30 nucleotides around the lesion. It is believed that DNA unwinding requires the helicase activity of Ercc2 and the ATPase activity of Ercc3 with the latter being regulated by Xpc. Subsequently, the Rpa trimeric complex together with Xpa are recruited; Rpa associates with single-stranded damaged DNA while Xpa, in addition to Rpa, also interacts with Xpc. Rpa stimulates recruitment of incision endonucleases Ercc4/XPF-Ercc1 complex and Ercc5/XPG. Ercc4-Ercc1 and Ercc5 cleave at the 5' and 3' to the lesion, respectively followed by release of Xpc and TFIIH. Rpa also interacts with and stimulates several DNA polymerases. Recruitment of Rfc complex, Pcna and DNA polymerase leads to release of Ercc4/XPF and initiation of repair synthesis which precedes the 3', Ercc5 mediated cleavage. Once Ercc5 is released, Rpa and the excised DNA fragment are also released. DNA synthesis s carried out by DNA polymerases delta, epsilon or kappa, depending on the state of the cell. Pcna is a trimeric clamp - a ring-shaped structure known to increase the processivity of replicative DNA polymerases and also needed in repair. Clamp assembly relies on the ATP-dependent action of the clamp loader ¿ the pentameric Rfc complex. The strand is sealed by DNA ligase Lig1 or Lig3-Xrcc1 complex. Post translational modifications (PMT) of molecules involved in NER and of histones, affect the proceedings of the pathway. Histone are components of chromatin whose relatively relaxed or compacted structure promotes or impedes access to DNA, respectively. Chromatin modification/remodeling is an integral part of DDR pathway. The ¿access-repair-restore¿ is the proposed model of DNA repair in the context of chromatin. Some NER proteins can modify chromatin and/or interact with modifiers or remodelers. Components of NER can also play a role in transcription, irrespective of genotoxic damage. In humans, inborn defects in several NER proteins, have been associated with skin cancer-prone and premature aging-like diseases. diagram_image: https://rgd.mcw.edu/pathway/PW0000130/nucleotide%20excision%20repair%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000130/nucleotide%20excision%20repair%20pathway/nucleotide%20excision%20repair%20pathway.gpp diagram_pathway_links: - id: PW:0001337 label: chromatin modification/remodeling pathway diagram_gene_links: - id: RGD:620247 label: Cetn2 - id: RGD:621889 label: Ddb1 - id: RGD:1310164 label: Ddb2 - id: RGD:1306992 label: Ercc1 - id: RGD:1309109 label: Ercc2 - id: RGD:1307139 label: Ercc3 - id: RGD:1560340 label: Ercc4 - id: RGD:1586176 label: Ercc5 - id: RGD:1311509 label: Ercc6 - id: RGD:1311570 label: Ercc8 - id: RGD:1308225 label: Gtf2h1 - id: RGD:1310499 label: Gtf2h2 - id: RGD:1307761 label: Hmgn1 - id: RGD:621424 label: Lig1 - id: RGD:1309875 label: Lig3 - id: RGD:3269 label: Pcna - id: RGD:620058 label: Polk - id: RGD:1562958 label: Rad23b - id: RGD:621217 label: Xab2 - id: RGD:1308769 label: Xpa - id: RGD:1305760 label: Xpc - id: RGD:619823 label: Xrcc1 diagram_chemicals: [] diagram_edges: - source: Cetn2 relation: associated_with target: Xpc - source: Ddb1 relation: associated_with target: Ddb2 - source: Ercc1 relation: associated_with target: Ercc4 - source: Ercc1 relation: associated_with target: Xpa - source: Ercc3 relation: associated_with target: Xpc - source: Ercc4 relation: associated_with target: Rpa complex - source: Ercc5 relation: associated_with target: Rpa complex - source: Ercc6 relation: associated_with target: Ercc8 - source: Ercc6 relation: associated_with target: stalled polrII complex - source: Ercc8 relation: associated_with target: Gtf2h2 - source: Ercc8 relation: associated_with target: Hmgn1 - source: Ercc8 relation: associated_with target: Xab2 - source: Gtf2h1 relation: associated_with target: Xpc - source: Lig3 relation: associated_with target: Xrcc1 - source: Pcna relation: associated_with target: Polk - source: Pcna relation: associated_with target: Rfc complex - source: Pcna relation: associated_with target: pold complex - source: Pcna relation: associated_with target: pole complex - source: Polk relation: associated_with target: Rpa complex - source: Rad23b relation: associated_with target: Xpc - source: Rpa complex relation: associated_with target: Xpa - source: pold complex relation: associated_with target: Rpa complex - source: pole complex relation: associated_with target: Rpa complex diagram_labels: - DNA incision - helix unwinding - stalled polrII complex - TFIIH complex diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/pold-complex2 label: pold complex - href: /wg/home/pathway2/molecular-pathways2/pole-complex label: pole complex - href: /wg/home/pathway2/molecular-pathways2/rfc-complex label: Rfc complex - href: /wg/home/pathway2/molecular-pathways2/rpa-complex2 label: Rpa complex references: - id: RGD:5129803 citation: Bowman GD, etal., FEBS Lett. 2005 Feb 7;579(4):863-7. - id: RGD:7246919 citation: 'Kamileri I, etal., Trends Genet. 2012 Nov;28(11):566-73. doi: 10.1016/j.tig.2012.06.004. 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