Repair of a DNA-protein crosslink by replication-coupled proteolysis

TY - JOUR

T1 - Repair of a DNA-protein crosslink by replication-coupled proteolysis

AU - Duxin, Julien P

AU - Dewar, James M

AU - Yardimci, Hasan

AU - Walter, Johannes C

N1 - Copyright © 2014 Elsevier Inc. All rights reserved.

PY - 2014/10/9

Y1 - 2014/10/9

N2 - 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 ζ. 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.

AB - 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 ζ. 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.

KW - Animals

KW - Cell Extracts

KW - DNA Adducts

KW - DNA Repair

KW - DNA Replication

KW - DNA-Directed DNA Polymerase

KW - Genomic Instability

KW - Ovum

KW - Xenopus

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

U2 - 10.1016/j.cell.2014.09.024

DO - 10.1016/j.cell.2014.09.024

M3 - Journal article

C2 - 25303529

SN - 0092-8674

VL - 159

SP - 346

EP - 357

JO - Cell

JF - Cell

IS - 2

ER -