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hSSB1 rapidly binds at the sites of DNA double-strand breaks and is required for the efficient recruitment of the MRN complex

Author:
Richard, Derek J., Savage, Kienan, Bolderson, Emma, Cubeddu, Liza, So, Sairei, Ghita, Mihaela, Chen, David J., White, Malcolm F., Richard, Kerry, Prise, Kevin M., Schettino, Giuseppe, Khanna, Kum Kum
Source:
Nucleic acids research 2011 v.39 no.5 pp. 1692-1702
ISSN:
0305-1048
Subject:
DNA damage, homologous recombination, interphase, resection, single-stranded DNA
Abstract:
hSSB1 is a newly discovered single-stranded DNA (ssDNA)-binding protein that is essential for efficient DNA double-strand break signalling through ATM. However, the mechanism by which hSSB1 functions to allow efficient signalling is unknown. Here, we show that hSSB1 is recruited rapidly to sites of double-strand DNA breaks (DSBs) in all interphase cells (G1, S and G2) independently of, CtIP, MDC1 and the MRN complex (Rad50, Mre11, NBS1). However expansion of hSSB1 from the DSB site requires the function of MRN. Strikingly, silencing of hSSB1 prevents foci formation as well as recruitment of MRN to sites of DSBs and leads to a subsequent defect in resection of DSBs as evident by defective RPA and ssDNA generation. Our data suggests that hSSB1 functions upstream of MRN to promote its recruitment at DSBs and is required for efficient resection of DSBs. These findings, together with previous work establish essential roles of hSSB1 in controlling ATM activation and activity, and subsequent DSB resection and homologous recombination (HR).
Agid:
2329998