Journal
NUCLEIC ACIDS RESEARCH
Volume 41, Issue 22, Pages 10268-10282Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt775
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Funding
- Ontario Early Researcher Award [ER07-04-157]
- Canadian Institutes of Health Research [MOP-86620]
- Ontario Graduate Scholarship
- Canadian Institutes of Health Research
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TRF1, a duplex telomeric DNA-binding protein, plays an important role in telomere metabolism. We have previously reported that a fraction of endogenous TRF1 can stably exist free of telomere chromatin when it is phosphorylated at T371 by Cdk1; however, the role of this telomere-free (pT371)TRF1 has yet to be fully characterized. Here we show that phosphorylated (pT371) TRF1 is recruited to sites of DNA damage, forming damage-induced foci in response to ionizing radiation (IR), etoposide and camptothecin. We find that IR-induced (pT371) TRF1 foci formation is dependent on the ATM- and Mre11/Rad50/Nbs1-mediated DNA damage response. While loss of functional BRCA1 impairs the formation of IR-induced (pT371) TRF1 foci, depletion of either 53BP1 or Rif1 stimulates IR-induced (pT371) TRF1 foci formation. In addition, we show that TRF1 depletion or the lack of its phosphorylation at T371 impairs DNA end resection and repair of nontelomeric DNA double-strand breaks by homologous recombination. The lack of TRF1 phosphorylation at T371 also hampers the activation of the G2/M checkpoint and sensitizes cells to PARP inhibition, IR and camptothecin. Collectively, these results reveal a novel but important function of phosphorylated (pT371) TRF1 in facilitating DNA double-strand break repair and the maintenance of genome integrity.
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