title: ATR suppresses telomere fragility and recombination but is dispensable for elongation of short telomeres by telomerase.
abstract: Telomere shortening caused by incomplete DNA replication is balanced by telomerase-mediated telomere extension, with evidence indicating that the shortest telomeres are preferred substrates in primary cells. Critically short telomeres are detected by the cellular DNA damage response (DDR) system. In budding yeast, the important DDR kinase Tel1 (homologue of ATM [ataxia telangiectasia mutated]) is vital for telomerase recruitment to short telomeres, but mammalian ATM is dispensable for this function. We asked whether closely related ATR (ATM and Rad3 related) kinase, which is important for preventing replicative stress and chromosomal breakage at common fragile sites, might instead fulfill this role. The newly created ATR-deficient Seckel mouse strain was used to examine the function of ATR in telomerase recruitment and telomere function. Telomeres were recently found to resemble fragile sites, and we show in this study that ATR has an important role in the suppression of telomere fragility and recombination. We also find that wild-type ATR levels are important to protect short telomeres from chromosomal fusions but do not appear essential for telomerase recruitment to short telomeres in primary mouse embryonic fibroblasts from the ATR-deficient Seckel mouse model. These results reveal a previously unnoticed role for mammalian ATR in telomere protection and stability.
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Centre, Madrid 28029, Spain.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: McNees
authors.forename: Agueda M
authors.initials: AM
authors.lastname: Tejera
authors.forename: Paula
authors.initials: P
authors.lastname: Martínez
authors.forename: Matilde
authors.initials: M
authors.lastname: Murga
authors.forename: Francisca
authors.initials: F
authors.lastname: Mulero
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D015996:Survival Rate; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019098:Telomerase