title: Phosphorylated (pT371)TRF1 is recruited to sites of DNA damage to facilitate homologous recombination and checkpoint activation.
abstract: 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.
authors.affiliation: Department of Biology, McMaster University, 1280 Main St. West, Hamilton, Ontario L8S4K1, Canada.
authors.forename: Megan
authors.initials: M
authors.lastname: McKerlie
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: Taylor R H
authors.initials: TR
authors.lastname: Mitchell
authors.forename: Florence R
authors.initials: FR
authors.lastname: Wilson
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Zhu
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D019313:BRCA1 Protein / Q000502:physiology; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D059565:G2 Phase Cell Cycle Checkpoints; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D010766:Phosphorylation; D059767:Recombinational DNA Repair; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D035321:Telomeric Repeat Binding Protein 1; D000071857:Tumor Suppressor p53-Binding Protein 1; D064007:Ataxia Telangiectasia Mutated Proteins