The ERCC1/XPF endonuclease is required for completion of homologous recombination at DNA replication forks stalled by inter-strand cross-links

Al-Minawi, Ali Z.; Lee, Yin-Fai; Håkansson, Daniel; Johansson, Fredrik; Lundin, Cecilia; Saleh‐Gohari, Nasrollah; Schultz, Niklas; Jenssen, Dag; Bryant, Helen E.; Meuth, Mark; Hinz, John M.; Helleday, Thomas

doi:10.1093/nar/gkp705

Cited by 80 publications

(72 citation statements)

References 59 publications

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“…We assessed the influence of the NER and HR pathway on cisplatin cytotoxicity in a BER-deficient background. ERCC1-XPF is a critical component of NER and also required in HR to complete ICL DNA repair (26,35). Down-regulation of ERCC1-XPF resulted in hypersensitivity to cisplatin in wild-type parental cells, consistent with previous studies (20,27).…”

Section: Discussionsupporting

confidence: 86%

“…Sensitivity-The structure-specific endonuclease, ERCC1-XPF, is required for incising the damaged DNA strand in NER and is also involved in HR (35). Due to the important role of ERCC1-XPF in the processing of cisplatin DNA adducts (20), we asked whether targeting this complex in BER-proficient and -deficient cells would affect cisplatin cytotoxicity.…”

Section: Down-regulation Of Ercc1-xpf Restores Cisplatinmentioning

confidence: 99%

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Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

Kothandapani

Dangeti

Brown

et al. 2011

Journal of Biological Chemistry

121

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Using isogenic mouse embryonic fibroblasts and human cancer cell lines, we show that cells defective in base excision repair (BER) display a cisplatin-specific resistant phenotype. This was accompanied by enhanced repair of cisplatin interstrand crosslinks (ICLs) and ICL-induced DNA double strand breaks, but not intrastrand adducts. Cisplatin induces abasic sites with a reduced accumulation in uracil DNA glycosylase (UNG) null cells. We show that cytosines that flank the cisplatin ICLs undergo preferential oxidative deamination in vitro, and AP endonuclease 1 (APE1) can cleave the resulting ICL DNA substrate following removal of the flanking uracil. We also show that DNA polymerase ␤ has low fidelity at the cisplatin ICL site after APE1 incision. Down-regulating ERCC1-XPF in BER-deficient cells restored cisplatin sensitivity. Based on our results, we propose a novel model in which BER plays a positive role in maintaining cisplatin cytotoxicity by competing with the productive cisplatin ICL DNA repair pathways.

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Section: Discussionsupporting

confidence: 86%

Section: Down-regulation Of Ercc1-xpf Restores Cisplatinmentioning

confidence: 99%

Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

Kothandapani

Dangeti

Brown

et al. 2011

Journal of Biological Chemistry

121

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“…The latter type of break is likely caused by HR-dependent repair between the broken and the intact sister chromatids, followed by defective resolution of recombination intermediates (33). Taking roles of SLX1 (21,26), XPF-ERCC1 (34)(35)(36), and MUS81-EME1 (37,38) in HR into account, our findings thus support the hypothesis that SLX4 deficiency causes impaired resolution of HR intermediates, possibly through the disruption of functional SLX4 complex, including these structure-specific endonucleases.…”

Section: Slx4 Is Essential For Cell Proliferationsupporting

confidence: 80%

Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway

Yamamoto

Kobayashi

Tsuda

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

178

156

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Interstrand cross-links (ICLs) block replication and transcription and thus are highly cytotoxic. In higher eukaryotes, ICLs processing involves the Fanconi anemia (FA) pathway and homologous recombination. Stalled replication forks activate the eight-subunit FA core complex, which ubiquitylates FANCD2-FANCI. Once it is posttranslationally modified, this heterodimer recruits downstream members of the ICL repairosome, including the FAN1 nuclease. However, ICL processing has been shown to also involve MUS81-EME1 and XPF-ERCC1, nucleases known to interact with SLX4, a docking protein that also can bind another nuclease, SLX1. To investigate the role of SLX4 more closely, we disrupted the SLX4 gene in avian DT40 cells. SLX4 deficiency caused cell death associated with extensive chromosomal aberrations, including a significant fraction of isochromatid-type breaks, with sister chromatids broken at the same site. SLX4 thus appears to play an essential role in cell proliferation, probably by promoting the resolution of interchromatid homologous recombination intermediates. Because ubiquitylation plays a key role in the FA pathway, and because the N-terminal region of SLX4 contains a ubiquitinbinding zinc finger (UBZ) domain, we asked whether this domain is required for ICL processing. We found that SLX4 −/− cells expressing UBZ-deficient SLX4 were selectively sensitive to ICL-inducing agents, and that the UBZ domain was required for interaction of SLX4 with ubiquitylated FANCD2 and for its recruitment to DNAdamage foci generated by ICL-inducing agents. Our findings thus suggest that ubiquitylated FANCD2 recruits SLX4 to DNA damage sites, where it mediates the resolution of recombination intermediates generated during the processing of ICLs.endonuclease | mitomycin C | cisplatin | DNA repair I nterstrand cross-links (ICLs) inhibit transcription and replication. Their considerable cytotoxicity has been ascribed primarily to their blockage of replication forks, and this phenomenon is believed to be responsible for the success of ICL-inducing agents, such as cisplatin and mitomycin-C (MMC), in cancer chemotherapy (1). ICL processing is complex, involving proteins from several distinct pathways of DNA metabolism. In higher organisms, ICL processing is orchestrated by the Fanconi anemia (FA) pathway (2, 3). Collision of replication forks with ICLs activates the ATR kinase, which in turn licenses the FANCL ubiquitin ligase subunit of the FA core complex (composed of FANCA, B, C, E, F, G, L and M proteins) to modify the FANCD2-FANCI heterodimer (2, 4-6). The monoubiquitylated FANCD2-FANCI complex is then targeted to chromatin (7,8), where it recruits downstream components of the repairosome, including the structure-specific nuclease FAN1 (9-12). However, ICL processing also requires other enzymes, such as the nucleases MUS81-EME1 and XPF-ERCC1, and how these are recruited to sites of damage in ICL repair is not known.The structure-specific endonucleases XPF-ERCC1 and MUS81-EME1, which are implicated in ICL repair and in the res...

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“…The 5′-3′ structure-specific endonuclease activity of the complex was subsequently shown to be also required for the Fanconi anemia (FA) pathway of interstrand crosslink repair (ICL-R), [1][2][3] as well as for homology-directed repair (HDR) of DNA double-strand breaks (DSB). [4][5][6][7] XPF is catalytically active, while ERCC1 tethers the activity of the complex to the site of repair through physical interactions with the core machinery complexes of several repair pathways (see ref. 8 for review).…”

Section: Introductionmentioning

confidence: 99%