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 and Claus Storgaard Sørensen ()
Additional contact information
Kasper Fugger: Biotech Research and Innovation Centre (BRIC), University of Copenhagen
Wai Kit Chu: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
Peter Haahr: Biotech Research and Innovation Centre (BRIC), University of Copenhagen
Arne Nedergaard Kousholt: Biotech Research and Innovation Centre (BRIC), University of Copenhagen
Halfdan Beck: Biotech Research and Innovation Centre (BRIC), University of Copenhagen
Miranda J. Payne: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
Katsuhiro Hanada: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
Ian D. Hickson: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
Claus Storgaard Sørensen: Biotech Research and Innovation Centre (BRIC), University of Copenhagen

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: 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.

Date: 2013
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms2395 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2395

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms2395

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().