AI Article Synopsis
- The study investigates the molecular processes that occur when DNA replication forks are disrupted, focusing on the role of the FBH1 helicase in this context.
- It finds that cells lacking FBH1 are resistant to the effects of the replication inhibitor hydroxyurea and show reduced activation of the tumor suppressor p53, indicating less DNA damage.
- The researchers also demonstrate that FBH1 works together with the MUS81 nuclease to create DNA double-strand breaks, which are necessary for killing cells under excessive replication stress.
Article 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.
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| http://dx.doi.org/10.1038/ncomms2395 | DOI Listing |
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