Reactome: A Curated Pathway Database

Formation of TC-NER Pre-Incision Complex

Stable Identifier
R-HSA-6781823
Type
Pathway
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

Formation of TC-NER pre-incision complex is initiated when the RNA polymerase II (RNA Pol II) complex stalls at a DNA damage site. The stalling is caused by misincorporation of a ribonucleotide opposite to a damaged base (Brueckner et al. 2007). Cockayne syndrome protein B (ERCC6, CSB) binds stalled RNA Pol II and recruits Cockayne syndrome protein A (ERCC8, CSA). ERCC8 is part of an ubiquitin ligase complex that also contains DDB1, CUL4A or CUL4B and RBX1. This complex is implicated in the regulation of TC-NER progression probably by ubiquitinating one or more factors involved in this pathway, which may include RNA Pol II and ERCC6 at the later stages of repair (Bregman et al. 1996, Fousteri et al. 2006, Groisman et al. 2006). XPA is recruited to the TC-NER site through its interaction with the TFIIH complex (Furuta et al. 2002, Ziani et al. 2014). The XAB2 complex, which probably regulates the accessibility of the DNA damage site through its RNA-DNA helicase activity, binds the TC-NER site via the interaction of its XAB2 subunit with RNA Pol II, ERCC6, ERCC8 and XPA (Nakatsu et al. 2000, Sollier et al. 2014). TCEA1 (TFIIS) is a transcription elongation factor that may facilitate backtracking of the stalled RNA Pol II, enabling access of repair proteins to the DNA damage site and promotes partial digestion of the 3' protruding end of the nascent mRNA transcript by the backtracked RNA Pol II, allowing resumption of RNA synthesis after damage removal (Donahue et al. 1994). Access to DNA damage site is also facilitated by chromatin remodelers HMGN1 (recruited to the TC-NER site through RNA Pol II and ERCC8-dependent manner) and histone acetyltransferase p300 (EP300), recruited to the TC-NER site through ERCC6-dependent manner (Birger et al. 2003, Fousteri et al. 2006). UVSSA protein interacts with ubiquitinated ERCC6 and RNA Pol II, recruiting ubiquitin protease USP7 to the TC-NER site and promoting ERCC6 stabilization (Nakazawa et al. 2012, Schwertman et al. 2012, Zhang et al. 2012, Fei and Chen 2012).

Literature References
PubMed ID Title Journal Year
12660172 Chromosomal protein HMGN1 enhances the rate of DNA repair in chromatin EMBO J. 2003
12208738 Transcription-coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cells Cancer Res. 2002
8078911 Transcript cleavage by RNA polymerase II arrested by a cyclobutane pyrimidine dimer in the DNA template Proc. Natl. Acad. Sci. U.S.A. 1994
17290000 CPD damage recognition by transcribing RNA polymerase II Science 2007
22466610 Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair Nat. Genet. 2012
16751180 CSA-dependent degradation of CSB by the ubiquitin-proteasome pathway establishes a link between complementation factors of the Cockayne syndrome Genes Dev. 2006
22466611 UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair Nat. Genet. 2012
16916636 Cockayne syndrome A and B proteins differentially regulate recruitment of chromatin remodeling and repair factors to stalled RNA polymerase II in vivo Mol. Cell 2006
25435140 Transcription-coupled nucleotide excision repair factors promote R-loop-induced genome instability Mol. Cell 2014
22902626 KIAA1530 protein is recruited by Cockayne syndrome complementation group protein A (CSA) to participate in transcription-coupled repair (TCR) J. Biol. Chem. 2012
25154395 Sequential and ordered assembly of a large DNA repair complex on undamaged chromatin J. Cell Biol. 2014
8876179 UV-induced ubiquitination of RNA polymerase II: a novel modification deficient in Cockayne syndrome cells Proc. Natl. Acad. Sci. U.S.A. 1996
10944529 XAB2, a novel tetratricopeptide repeat protein involved in transcription-coupled DNA repair and transcription J. Biol. Chem. 2000
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