Understanding nucleotide excision repair and its roles in cancer and ageing

Abstract

Nucleotide excision repair (NER) eliminates various structurally unrelated DNA lesions by a multiwise 'cut and patch'-type reaction. The global genome NER (GG-NER) subpathway prevents mutagenesis by probing the genome for helix-distorting lesions, whereas transcription-coupled NER (TC-NER) removes transcription-blocking lesions to permit unperturbed gene expression, thereby preventing cell death. Consequently, defects in GG-NER result in cancer predisposition, whereas defects in TC-NER cause a variety of diseases ranging from ultraviolet radiation-sensitive syndrome to severe premature ageing conditions such as Cockayne syndrome. Recent studies have uncovered new aspects of DNA-damage detection by NER, how NER is regulated by extensive post-translational modifications, and the dynamic chromatin interactions that control its efficiency. Based on these findings, a mechanistic model is proposed that explains the complex genotype-phenotype correlations of transcription-coupled repair disorders.

Association of Genetic Variations in XRCC1 and ERCC1 Genes with Sporadic Breast Cancer

“…During exposure of DNA to IR, the doublestranded DNA may be broken and this increases the risk of BC progress (6). In humans, base excision repair (BER) and Nucleotide Excision Repair (NER) comprised of the two most common DNA repair mechanisms (7,8). In BER systems, there are eleven DNA damage special proteins that contribute to a specific function.…”

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

“…These lesions are all repaired by the nucleotide excision repair (NER) pathway. Two forms of NER exist, global genomic (GG)-NER, which recognizes lesions occurring throughout the genome, and transcription-coupled (TC)-NER, which recognizes lesions causing arrest of RNA Polymerase II during transcriptional elongation (Marteijn et al 2014). Although the initial DNA damage recognition factors for GG-and TC-NER vary depending on the recognizing pathway and the type of lesion involved, all converge on the assembly of the TFIIH complex at the site of damage, and unwinding of DNA in an extended region around the damage site; this extended section of ssDNA is stabilized by interaction with RPA.…”

“…Although the initial DNA damage recognition factors for GG-and TC-NER vary depending on the recognizing pathway and the type of lesion involved, all converge on the assembly of the TFIIH complex at the site of damage, and unwinding of DNA in an extended region around the damage site; this extended section of ssDNA is stabilized by interaction with RPA. The ssDNA strand containing the lesion is excised at both ends by XPF and XPG, and the PCNA replicative helicase recruits DNA polymerases δ, ε D r a f t 27 or κ, one or more of which fills the ssDNA gap prior to ligation of the repaired DNA (Marteijn et al 2014). …”

Architecture of the human XPC DNA repair and stem cell coactivator complex

“…Similarly, proper use and expression of this essential genomic information is regulated by a host of transcription factors, chromatin remodelers, and epigenetic modifiers and readers (1). The Xeroderma pigmentosum complementation group C (XPC) protein complex performs crucial roles in both of these capacities by participating in nucleotide excision repair (NER) (2) and base excision repair (BER) (3), as well as transcriptional regulation (4) and other processes (5).…”

“…The XPC complex is one of seven XP complementation groups A-G and is composed of the 125-kDa XPC, the 58-kDa RAD23B (Rad23 homolog B; also known as HHR23B), and the 18-kDa CETN2 (Centrin2) subunits (2). RAD23B and CETN2 associate tightly with XPC and stabilize both its DNA repair (6)(7)(8)(9)(10) and stem cell coactivator functions (4).…”