FBH1 Catalyzes Regression of Stalled Replication Forks

Kasper Fugger; Martin Mistrik; Kai J Neelsen; Qi Yao; Ralph Zellweger; Arne Nedergaard Kousholt; Peter Haahr; Wai Kit Chu; Jiri Bartek; Massimo Lopes; Ian D Hickson; Claus Storgaard Sørensen

doi:10.1016/j.celrep.2015.02.028

FBH1 Catalyzes Regression of Stalled Replication Forks

Kasper Fugger, Martin Mistrik, Kai J Neelsen, Qi Yao, Ralph Zellweger, Arne Nedergaard Kousholt, Peter Haahr, Wai Kit Chu, Jiri Bartek, Massimo Lopes, Ian D Hickson, Claus Storgaard Sørensen

56 Citations (Scopus)

Abstract

DNA replication fork perturbation is a major challenge to the maintenance of genome integrity. It has been suggested that processing of stalled forks might involve fork regression, in which the fork reverses and the two nascent DNA strands anneal. Here, we show that FBH1 catalyzes regression of a model replication fork in vitro and promotes fork regression in vivo in response to replication perturbation. Cells respond to fork stalling by activating checkpoint responses requiring signaling through stress-activated protein kinases. Importantly, we show that FBH1, through its helicase activity, is required for early phosphorylation of ATM substrates such as CHK2 and CtIP as well as hyperphosphorylation of RPA. These phosphorylations occur prior to apparent DNA double-strand break formation. Furthermore, FBH1-dependent signaling promotes checkpoint control and preserves genome integrity. We propose a model whereby FBH1 promotes early checkpoint signaling by remodeling of stalled DNA replication forks.

Original language	English
Journal	Cell Reports
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2015.02.028
Publication status	Published - 17 Mar 2015

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title = "FBH1 Catalyzes Regression of Stalled Replication Forks",

abstract = "DNA replication fork perturbation is a major challenge to the maintenance of genome integrity. It has been suggested that processing of stalled forks might involve fork regression, in which the fork reverses and the two nascent DNA strands anneal. Here, we show that FBH1 catalyzes regression of a model replication fork in vitro and promotes fork regression in vivo in response to replication perturbation. Cells respond to fork stalling by activating checkpoint responses requiring signaling through stress-activated protein kinases. Importantly, we show that FBH1, through its helicase activity, is required for early phosphorylation of ATM substrates such as CHK2 and CtIP as well as hyperphosphorylation of RPA. These phosphorylations occur prior to apparent DNA double-strand break formation. Furthermore, FBH1-dependent signaling promotes checkpoint control and preserves genome integrity. We propose a model whereby FBH1 promotes early checkpoint signaling by remodeling of stalled DNA replication forks.",

author = "Kasper Fugger and Martin Mistrik and Neelsen, {Kai J} and Qi Yao and Ralph Zellweger and Kousholt, {Arne Nedergaard} and Peter Haahr and Chu, {Wai Kit} and Jiri Bartek and Massimo Lopes and Hickson, {Ian D} and S{\o}rensen, {Claus Storgaard}",

year = "2015",

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doi = "10.1016/j.celrep.2015.02.028",

language = "English",

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T1 - FBH1 Catalyzes Regression of Stalled Replication Forks

AU - Fugger, Kasper

AU - Mistrik, Martin

AU - Neelsen, Kai J

AU - Yao, Qi

AU - Zellweger, Ralph

AU - Kousholt, Arne Nedergaard

AU - Haahr, Peter

AU - Chu, Wai Kit

AU - Bartek, Jiri

AU - Lopes, Massimo

AU - Hickson, Ian D

AU - Sørensen, Claus Storgaard

PY - 2015/3/17

Y1 - 2015/3/17

N2 - DNA replication fork perturbation is a major challenge to the maintenance of genome integrity. It has been suggested that processing of stalled forks might involve fork regression, in which the fork reverses and the two nascent DNA strands anneal. Here, we show that FBH1 catalyzes regression of a model replication fork in vitro and promotes fork regression in vivo in response to replication perturbation. Cells respond to fork stalling by activating checkpoint responses requiring signaling through stress-activated protein kinases. Importantly, we show that FBH1, through its helicase activity, is required for early phosphorylation of ATM substrates such as CHK2 and CtIP as well as hyperphosphorylation of RPA. These phosphorylations occur prior to apparent DNA double-strand break formation. Furthermore, FBH1-dependent signaling promotes checkpoint control and preserves genome integrity. We propose a model whereby FBH1 promotes early checkpoint signaling by remodeling of stalled DNA replication forks.

AB - DNA replication fork perturbation is a major challenge to the maintenance of genome integrity. It has been suggested that processing of stalled forks might involve fork regression, in which the fork reverses and the two nascent DNA strands anneal. Here, we show that FBH1 catalyzes regression of a model replication fork in vitro and promotes fork regression in vivo in response to replication perturbation. Cells respond to fork stalling by activating checkpoint responses requiring signaling through stress-activated protein kinases. Importantly, we show that FBH1, through its helicase activity, is required for early phosphorylation of ATM substrates such as CHK2 and CtIP as well as hyperphosphorylation of RPA. These phosphorylations occur prior to apparent DNA double-strand break formation. Furthermore, FBH1-dependent signaling promotes checkpoint control and preserves genome integrity. We propose a model whereby FBH1 promotes early checkpoint signaling by remodeling of stalled DNA replication forks.

U2 - 10.1016/j.celrep.2015.02.028

DO - 10.1016/j.celrep.2015.02.028

M3 - Journal article

C2 - 25772361

SN - 2639-1856

JO - Cell Reports

JF - Cell Reports

ER -

FBH1 Catalyzes Regression of Stalled Replication Forks

Abstract

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