FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

Kasper Fugger; Wai Kit Chu; Peter Haahr; Arne Nedergaard Kousholt; Halfdan Beck; Miranda J Payne; Katsuhiro Hanada; Ian D Hickson; Claus Storgaard Sørensen

doi:10.1038/ncomms2395

FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

Kasper Fugger, Wai Kit Chu, Peter Haahr, Arne Nedergaard Kousholt, Halfdan Beck, Miranda J Payne, Katsuhiro Hanada, Ian D Hickson, Claus Storgaard Sørensen

58 Citationer (Scopus)

Abstract

The molecular events occurring following the disruption of DNA replication forks are poorly characterized, despite extensive use of replication inhibitors such as hydroxyurea in the treatment of malignancies. Here, we identify a key role for the FBH1 helicase in mediating DNA double-strand break formation following replication inhibition. We show that FBH1-deficient cells are resistant to killing by hydroxyurea, and exhibit impaired activation of the pro-apoptotic factor p53, consistent with decreased DNA double-strand break formation. Similar findings were obtained in murine ES cells carrying disrupted alleles of Fbh1. We also show that FBH1 through its helicase activity co-operates with the MUS81 nuclease in promoting the endonucleolytic DNA cleavage following prolonged replication stress. Accordingly, MUS81 and EME1-depleted cells show increased resistance to the cytotoxic effects of replication stress. Our data suggest that FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA double-strand breaks.

Originalsprog	Engelsk
Tidsskrift	Nature Communications
Vol/bind	4
Sider (fra-til)	1423
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms2395
Status	Udgivet - 2013

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10.1038/ncomms2395

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title = "FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress",

abstract = "The molecular events occurring following the disruption of DNA replication forks are poorly characterized, despite extensive use of replication inhibitors such as hydroxyurea in the treatment of malignancies. Here, we identify a key role for the FBH1 helicase in mediating DNA double-strand break formation following replication inhibition. We show that FBH1-deficient cells are resistant to killing by hydroxyurea, and exhibit impaired activation of the pro-apoptotic factor p53, consistent with decreased DNA double-strand break formation. Similar findings were obtained in murine ES cells carrying disrupted alleles of Fbh1. We also show that FBH1 through its helicase activity co-operates with the MUS81 nuclease in promoting the endonucleolytic DNA cleavage following prolonged replication stress. Accordingly, MUS81 and EME1-depleted cells show increased resistance to the cytotoxic effects of replication stress. Our data suggest that FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA double-strand breaks.",

keywords = "Alleles, Animals, Blotting, Southern, Cell Death, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA Helicases, DNA Replication, DNA-Binding Proteins, Doxycycline, Embryonic Stem Cells, Endonucleases, F-Box Proteins, Humans, Mice, RNA, Small Interfering, Signal Transduction, Stress, Physiological",

author = "Kasper Fugger and Chu, {Wai Kit} and Peter Haahr and Kousholt, {Arne Nedergaard} and Halfdan Beck and Payne, {Miranda J} and Katsuhiro Hanada and Hickson, {Ian D} and S{\o}rensen, {Claus Storgaard}",

year = "2013",

doi = "10.1038/ncomms2395",

language = "English",

volume = "4",

pages = "1423",

journal = "Nature Communications",

issn = "2041-1723",

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TY - JOUR

T1 - FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

AU - Fugger, Kasper

AU - Chu, Wai Kit

AU - Haahr, Peter

AU - Kousholt, Arne Nedergaard

AU - Beck, Halfdan

AU - Payne, Miranda J

AU - Hanada, Katsuhiro

AU - Hickson, Ian D

AU - Sørensen, Claus Storgaard

PY - 2013

Y1 - 2013

N2 - The molecular events occurring following the disruption of DNA replication forks are poorly characterized, despite extensive use of replication inhibitors such as hydroxyurea in the treatment of malignancies. Here, we identify a key role for the FBH1 helicase in mediating DNA double-strand break formation following replication inhibition. We show that FBH1-deficient cells are resistant to killing by hydroxyurea, and exhibit impaired activation of the pro-apoptotic factor p53, consistent with decreased DNA double-strand break formation. Similar findings were obtained in murine ES cells carrying disrupted alleles of Fbh1. We also show that FBH1 through its helicase activity co-operates with the MUS81 nuclease in promoting the endonucleolytic DNA cleavage following prolonged replication stress. Accordingly, MUS81 and EME1-depleted cells show increased resistance to the cytotoxic effects of replication stress. Our data suggest that FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA double-strand breaks.

AB - The molecular events occurring following the disruption of DNA replication forks are poorly characterized, despite extensive use of replication inhibitors such as hydroxyurea in the treatment of malignancies. Here, we identify a key role for the FBH1 helicase in mediating DNA double-strand break formation following replication inhibition. We show that FBH1-deficient cells are resistant to killing by hydroxyurea, and exhibit impaired activation of the pro-apoptotic factor p53, consistent with decreased DNA double-strand break formation. Similar findings were obtained in murine ES cells carrying disrupted alleles of Fbh1. We also show that FBH1 through its helicase activity co-operates with the MUS81 nuclease in promoting the endonucleolytic DNA cleavage following prolonged replication stress. Accordingly, MUS81 and EME1-depleted cells show increased resistance to the cytotoxic effects of replication stress. Our data suggest that FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA double-strand breaks.

KW - Alleles

KW - Animals

KW - Blotting, Southern

KW - Cell Death

KW - Cell Line, Tumor

KW - DNA Breaks, Double-Stranded

KW - DNA Helicases

KW - DNA Replication

KW - DNA-Binding Proteins

KW - Doxycycline

KW - Embryonic Stem Cells

KW - Endonucleases

KW - F-Box Proteins

KW - Humans

KW - Mice

KW - RNA, Small Interfering

KW - Signal Transduction

KW - Stress, Physiological

U2 - 10.1038/ncomms2395

DO - 10.1038/ncomms2395

M3 - Journal article

C2 - 23361013

SN - 2041-1723

VL - 4

SP - 1423

JO - Nature Communications

JF - Nature Communications

ER -

FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

Abstract

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