Regulation of endonuclease activity in human nucleotide excision repair

Abstract

Nucleotide excision repair (NER) is a DNA repair pathway that is responsible for removing a variety of lesions caused by harmful UV light, chemical carcinogens, and environmental mutagens from DNA. NER involves the concerted action of over 30 proteins that sequentially recognize a lesion, excise it in the form of an oligonucleotide, and fill in the resulting gap by repair synthesis. ERCC1-XPF and XPG are structure-specific endonucleases responsible for carrying out the incisions 5′ and 3′ to the damage respectively, culminating in the release of the damaged oligonucleotide. This review focuses on the recent work that led to a greater understanding of how the activities of ERCC1-XPF and XPG are regulated in NER to prevent unwanted cuts in DNA or the persistence of gaps after incision that could result in harmful, cytotoxic DNA structures.

Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

“…Originally linked to nucleotide excision repair, XPF, its binding partner ERCC1, and its loading factor XPA are also implicated in repair of ICLs, in SSA, homologous recombination, and telomere maintenance (Bogliolo et al 2013;Kashiyama et al 2013). XPF appears to be particularly important to trim unpaired ssDNA at the boundaries of limited homology domains and cleaves the 39 end of nonhomologous flaps (Paques and Haber 1997;Hollingsworth and Brill 2004;Fagbemi et al 2011;Schwartz and Heyer 2011;Mazon et al 2012). The role of XPF in meiosis varies considerably in different species.…”

“…The canonical model for NER suggests that upon recognition of helix-distorting lesions, the DNA is unwound to form a bubble around the damage. XPA (SpRhp14) loads XPF (SpRad16) and ERCC1 (SpSwi10); XPF cleaves at the 59 end of the bubble while XPG (SpRad13), another endonuclease, cleaves at the 39 end to remove the offending segment (Fagbemi et al 2011;Schwartz and Heyer 2011). Thus, Schizosaccharomyces pombe rad16 mutants show a decrease in (6-4) photoproduct excision (McCready et al 1993;Carr et al 1994).…”

Associations of ERCC4 rs1800067 Polymorphism with Cancer Risk: an Updated Meta-analysis

“…Excision repair cross-complementation group 4 (ERCC4), alternatively known as XPF, is an important member of NER system. The XPF-ERCC1 heterodimer is responsible for the 5' incision of the dual incision process in the NER pathway (Fagbemi et al, 2011). Besides, the XPF-ERCC1 heterodimer also exerts an important role in maintaining telomere stability and repairing interstrand cross-links (Niedernhofer et al, 2004).…”

Multiple DNA Binding Domains Mediate the Function of the ERCC1-XPF Protein in Nucleotide Excision Repair

“…The activity of these enzymes needs to be tightly regulated since they might otherwise inadvertently fragment DNA (1). One of the most important pathways depending on the action of endonucleases is nucleotide excision repair (NER), 3 which addresses lesions induced by UV light, environmental mutagens and certain cancer chemotherapeutic agents.…”