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

Julien P Duxin; James M Dewar; Hasan Yardimci; Johannes C Walter

doi:10.1016/j.cell.2014.09.024

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

Julien P Duxin, James M Dewar, Hasan Yardimci, Johannes C Walter

112 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Cell
Vol/bind	159
Udgave nummer	2
Sider (fra-til)	346-57
Antal sider	12
ISSN	0092-8674
DOI	https://doi.org/10.1016/j.cell.2014.09.024
Status	Udgivet - 9 okt. 2014
Udgivet eksternt	Ja

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10.1016/j.cell.2014.09.024

http://www.cell.com/article/S0092867414011738/pdf

Citationsformater

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title = "Repair of a DNA-protein crosslink by replication-coupled proteolysis",

abstract = "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.",

keywords = "Animals, Cell Extracts, DNA Adducts, DNA Repair, DNA Replication, DNA-Directed DNA Polymerase, Genomic Instability, Ovum, Xenopus, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.",

author = "Duxin, {Julien P} and Dewar, {James M} and Hasan Yardimci and Walter, {Johannes C}",

year = "2014",

month = oct,

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doi = "10.1016/j.cell.2014.09.024",

language = "English",

volume = "159",

pages = "346--57",

journal = "Cell",

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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

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 -

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

Abstract

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