Repair of a DNA-Protein Crosslink by Replication-Coupled Proteolysis

被引:182
作者
Duxin, Julien P. [1 ]
Dewar, James M. [1 ]
Yardimci, Hasan [2 ]
Walter, Johannes C. [1 ,3 ]
机构
[1] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
[2] Imperial Canc Res Fund, Clare Hall Labs, London Res Inst, Canc Res UK, S Mimms EN6 3LD, Herts, England
[3] Howard Hughes Med Inst, Chevy Chase, MD USA
关键词
NUCLEOTIDE EXCISION-REPAIR; XENOPUS EGG EXTRACTS; FANCONI-ANEMIA; HOMOLOGOUS RECOMBINATION; MAMMALIAN-CELLS; ABASIC SITES; FORMALDEHYDE; MECHANISM; HELICASE; PATHWAY;
D O I
10.1016/j.cell.2014.09.024
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
DNA-protein crosslinks (DPCs) are caused by environmental, endogenous, and chemotherapeutic agents and pose a severe threat to genome stability. We use Xenopus egg extracts to recapitulate DPC repair in vitro and show that this process is coupled to DNA replication. A DPC on the leading strand template arrests the replisome by stalling the CMG helicase. The DPC is then degraded on DNA, yielding a peptide-DNA adduct that is bypassed by CMG. The leading strand subsequently resumes synthesis, stalls again at the adduct, and then progresses past the adduct using DNA polymerase zeta. A DPC on the lagging strand template only transiently stalls the replisome, but it too is degraded, allowing Okazaki fragment bypass. Our experiments describe a versatile, proteolysis-based mechanism of S phase DPC repair that avoids replication fork collapse.
引用
收藏
页码:346 / 357
页数:12
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