Replication Fork Reversal during DNA Interstrand Crosslink Repair Requires CMG Unloading

被引：60

作者：

Amunugama, Ravindra ^{[1
,2
]}

Willcox, Smaranda ^{[3
]}

Wu, R. Alex ^{[1
,2
]}

Abdullah, Ummi B. ^{[4
]}

El-Sagheer, Afaf H. ^{[5
]}

Brown, Tom ^{[5
,6
]}

McHugh, Peter J. ^{[4
]}

Griffith, Jack D. ^{[3
]}

Walter, Johannes C. ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA

[2] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[3] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[4] Univ Oxford, Weatherall Inst Mol Med, Dept Oncol, Oxford OX3 9DS, England

[5] Univ Oxford, Dept Chem, Oxford OX1 3TA, England

[6] Univ Oxford, Dept Oncol, Old Rd Campus Res Bldg, Oxford OX3 7DQ, England

来源：

CELL REPORTS | 2018年 / 23卷 / 12期

基金：

英国生物技术与生命科学研究理事会;

关键词：

FANCONI-ANEMIA PATHWAY; BRCA2-DEFICIENT CELLS; MAMMALIAN-CELLS; MECHANISM; PROMOTES; HELICASE; DEGRADATION; REGRESSION; ALDEHYDES; NUCLEUS;

D O I：

10.1016/j.celrep.2018.05.061

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

DNA interstrand crosslinks (ICLs) are extremely cytotoxic, but the mechanism of their repair remains incompletely understood. Using Xenopus egg extracts, we previously showed that repair of a cisplatin ICL is triggered when two replication forks converge on the lesion. After CDC45/MCM2-7/GINS (CMG) ubiquitylation and unloading by the p97 segregase, FANCI-FANCD2 promotes DNA incisions by XPF-ERCC1, leading to ICL unhooking. Here, we report that, during this cell-free ICL repair reaction, one of the two converged forks undergoes reversal. Fork reversal fails when CMG unloading is inhibited, but it does not require FANCI-FANCD2. After one fork has undergone reversal, the opposing fork that still abuts the ICL undergoes incisions. Our data show that replication fork reversal at an ICL requires replisome disassembly. We present a revised model of ICL repair that involves a reversed fork intermediate.

引用

页码：3419 / 3428

页数：10

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