Journal
JOURNAL OF CELL BIOLOGY
Volume 188, Issue 5, Pages 639-652Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200908136
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Funding
- National Health and Medical Research Council of Australia
- Spanish Ministry of Science and Education
- Fondo de Investigaciones Sanitarias
- Spanish Ministry of Innovation and Science
- Consolider-Ingenio 2010 Program
- Regional Government of Madrid
- European Union
- Spanish Association Against Cancer
- Spanish Ministry of Science
- Epigenome Network of Excellence
- European Research Council
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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.
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