» Articles » PMID: 23361013

FBH1 Co-operates with MUS81 in Inducing DNA Double-strand Breaks and Cell Death Following Replication Stress

Overview
Journal Nat Commun
Specialty Biology
Date 2013 Jan 31
PMID 23361013
Citations 55
Authors
Affiliations
Soon will be listed here.
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.

Citing Articles

Concurrent D-loop cleavage by Mus81 and Yen1 yields half-crossover precursors.

Carreira R, Lama-Diaz T, Crugeiras M, Aguado F, Sebesta M, Krejci L Nucleic Acids Res. 2024; 52(12):7012-7030.

PMID: 38832625 PMC: 11229367. DOI: 10.1093/nar/gkae453.


FBH1 deficiency sensitizes cells to WEE1 inhibition by promoting mitotic catastrophe.

Jennings L, Walters H, McCraw T, Turner J, Mason J DNA Repair (Amst). 2023; 133:103611.

PMID: 38103522 PMC: 10872337. DOI: 10.1016/j.dnarep.2023.103611.


3-AP inhibits the growth of human osteosarcoma by decreasing the activity of the iron-dependent pathway.

Huang S, Zhang D, Yi X, Liu C, Jian C, Yu A Med Oncol. 2023; 40(12):353.

PMID: 37952032 DOI: 10.1007/s12032-023-02215-2.


Analysis and comparisons of gene expression changes in patient- derived neurons from ROHHAD, CCHS, and PWS.

Victor A, Hedgecock T, Donaldson M, Johnson D, Rand C, Weese-Mayer D Front Pediatr. 2023; 11:1090084.

PMID: 37234859 PMC: 10206321. DOI: 10.3389/fped.2023.1090084.


Molecular insight into the PCNA-binding mode of FBH1.

Liu J, Chaves-Arquero B, Wei P, Tencer A, Ruiz-Albor A, Zhang G Structure. 2023; 31(5):511-517.e3.

PMID: 36990095 PMC: 10727010. DOI: 10.1016/j.str.2023.03.004.


References
1.
Atkinson J, McGlynn P . Replication fork reversal and the maintenance of genome stability. Nucleic Acids Res. 2009; 37(11):3475-92. PMC: 2699526. DOI: 10.1093/nar/gkp244. View

2.
Kim J, Kim J, Lee S, Kim D, Kang H, Bae S . The novel human DNA helicase hFBH1 is an F-box protein. J Biol Chem. 2002; 277(27):24530-7. DOI: 10.1074/jbc.M201612200. View

3.
Johnson C, Forster T, Winterford C, Allan D . Hydroxyurea induces apoptosis and regular DNA fragmentation in a Burkitt's lymphoma cell line. Biochim Biophys Acta. 1992; 1136(1):1-4. DOI: 10.1016/0167-4889(92)90076-n. View

4.
Sartori A, Lukas C, Coates J, Mistrik M, Fu S, Bartek J . Human CtIP promotes DNA end resection. Nature. 2007; 450(7169):509-14. PMC: 2409435. DOI: 10.1038/nature06337. View

5.
Allen C, Ashley A, Hromas R, Nickoloff J . More forks on the road to replication stress recovery. J Mol Cell Biol. 2011; 3(1):4-12. PMC: 3030971. DOI: 10.1093/jmcb/mjq049. View