Molecular Mechanisms of Mammalian Global Genome Nucleotide Excision Repair

Gillet, Ludovic; Schärer, Orlando D.

doi:10.1021/cr040483f

Cited by 559 publications

(549 citation statements)

References 379 publications

(754 reference statements)

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“…Very little is known about the role of the helicase‐like domain, but it is important for nuclease activity (Bowles et al , 2012). The function of XPF‐ERCC1 in NER, a pathway that removes helix distorting lesions, has been extensively studied (Gillet & Schärer, 2006; Friedberg, 2011). After damage recognition by upstream NER factors, XPF‐ERCC1 is recruited to the lesion by XPA and excises a short oligo containing the damage in collaboration with another nuclease XPG (Huang et al , 1992; Li et al , 1995; Spivak, 2015).…”

Section: Introductionmentioning

confidence: 99%

Recruitment and positioning determine the specific role of the XPF ‐ ERCC 1 endonuclease in interstrand crosslink repair

et al. 2017

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XPF‐ERCC1 is a structure‐specific endonuclease pivotal for several DNA repair pathways and, when mutated, can cause multiple diseases. Although the disease‐specific mutations are thought to affect different DNA repair pathways, the molecular basis for this is unknown. Here we examine the function of XPF‐ERCC1 in DNA interstrand crosslink (ICL) repair. We used Xenopus egg extracts to measure both ICL and nucleotide excision repair, and we identified mutations that are specifically defective in ICL repair. One of these separation‐of‐function mutations resides in the helicase‐like domain of XPF and disrupts binding to SLX4 and recruitment to the ICL. A small deletion in the same domain supports recruitment of XPF to the ICL, but inhibited the unhooking incisions most likely by disrupting a second, transient interaction with SLX4. Finally, mutation of residues in the nuclease domain did not affect localization of XPF‐ERCC1 to the ICL but did prevent incisions on the ICL substrate. Our data support a model in which the ICL repair‐specific function of XPF‐ERCC1 is dependent on recruitment, positioning and substrate recognition.

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Section: Introductionmentioning

confidence: 99%

Recruitment and positioning determine the specific role of the XPF ‐ ERCC 1 endonuclease in interstrand crosslink repair

et al. 2017

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“…However, the results of studies on XPD polymorphisms with regard to a variety of human cancers remain contradictory [22,26,27]. The XPF gene encodes a protein which, together with ERCC1, creates the 5'endonuclease [28]. The results of studies on XPF and ERCC1 variants and the risk of cancer are also contradictory.…”

Section: Introductionmentioning

confidence: 99%

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual’s susceptibility to sporadic colorectal cancer

et al. 2011

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Abstract:Background: Epidemiological data show that colorectal cancer (CRC) is the second most frequent malignancy worldwide. The involvement of "minor impact genes" such as XME and DNA-repair genes in the etiology of sporadic cancer has been postulated by other authors.Aim: we focused on analyzing polymorphisms in DNA-repair genes in CRC. We considered the following genes involved in DNA-repair pathways: base excision repair (OGG1 Ser326Cys, XRCC1 Trp194Arg and Arg399Gln); nucleotide excision repair [XPA (-4)G/A, XPC C/A (i11) and A33512C (Lys939Gln), XPD Asp312Asn and A18911CMaterial and methods: The study group consisted of 133 patients diagnosed with sporadic CRC, while the control group was composed of 100 age-matched non-cancer volunteers. Genotyping was performed by PCR and PCR-RFLP. Fisher's exact test with a Bonferroni correction for multiple testing was used.Results: We found that: i) XPC C/A (i11) heterozygous variant is associated with increased risk of CRC [OR is 2.07 (95% CI 1.1391,3.7782) p=0.038], ii) XPD A18911C (Lys751Gln) is associated with decreased risk of CRC [OR=0.4497, (95% CI 0.2215,0,9131) p=0.031] for an individual with at least one A allele at this locus. Conclusions:1. the XPC C/A (i11) genotype is associated with an increased risk of sporadic colorectal cancer.2. the NER pathway has been highlighted in our study, as a most important in modulation of individual susceptibility to sCRC.

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“…There are two sub-pathways of NER. Global genome repair (GGR) is a relatively slow process that removes damage throughout the genome [7]. Transcription-coupled repair (TCR) is a more rapid process that removes damage specifically from the transcribed strand of genes that are being actively transcribed [8].…”

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confidence: 99%

A semi-automated non-radioactive system for measuring recovery of RNA synthesis and unscheduled DNA synthesis using ethynyluracil derivatives

et al. 2010

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Nucleotide excision repair (NER) removes the major UV photolesions from cellular DNA. In humans, compromised NER activity is the cause of several photosensitive diseases, one of which is the skin-cancer predisposition disorder, xeroderma pigmentosum (XP). Two assays commonly used in measurement of NER activity are 'Unscheduled DNA synthesis (UDS)', and 'Recovery of RNA synthesis (RRS)', the latter being a specific measure of the transcription-coupled repair sub-pathway of NER. Both assays are key techniques for research in NER as well as in diagnoses of NER-related disorders. Until very recently, reliable methods for these assays involved measurements of incorporation of radio-labeled nucleosides. We have established non-radioactive procedures for determining UDS and RRS levels by incorporation of recently-developed alkyne-conjugated nucleoside analogues, 5-ethynyl-2'-deoxyuridine (EdU) and 5-ethynyuridine (EU). EdU and EU are respectively used as alternatives for 3 Hthymidine in UDS and for 3 H-uridine in RRS. Based on these alkyne-nucleosides and an integrated image analyser, we have developed a semi-automated assay system for NERactivity. We demonstrate the utility of this system for NER-activity assessments of lymphoblastoid samples as well as primary fibroblasts. Potential use of the system for largescale siRNA screening for novel NER defects as well as for routine XP diagnosis are also considered.

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Molecular Mechanisms of Mammalian Global Genome Nucleotide Excision Repair

Cited by 559 publications

References 379 publications

Recruitment and positioning determine the specific role of the XPF ‐ ERCC 1 endonuclease in interstrand crosslink repair

Recruitment and positioning determine the specific role of the XPF ‐ ERCC 1 endonuclease in interstrand crosslink repair

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual’s susceptibility to sporadic colorectal cancer

A semi-automated non-radioactive system for measuring recovery of RNA synthesis and unscheduled DNA synthesis using ethynyluracil derivatives

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