FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress
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FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress. / Fugger, Kasper; Chu, Wai Kit; Haahr, Peter; Kousholt, Arne Nedergaard; Beck, Halfdan; Payne, Miranda J; Hanada, Katsuhiro; Hickson, Ian D; Sørensen, Claus Storgaard.
In: Nature Communications, Vol. 4, 2013, p. 1423.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 4
SP - 1423
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
ER -
ID: 47453610