期刊
EMBO JOURNAL
卷 29, 期 13, 页码 2230-2241出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/emboj.2010.58
关键词
chromosomes; DNA damage; telomeres
资金
- MDACC
- NASA [NNJ04HD83G, NNX08AB65G]
- NCI [CA052461, RO1 CA129037]
- NIA [RO1 AG028888]
- Welch Foundation
- Susan G Koman Race for the Cure Foundation
- Abraham and Phyllis Katz Foundation
- Michael Kadoorie Cancer
- Association pour la Recherche sur le Cancer
- European Union [Health-F2-2007-200950]
- NASA [NNX08AB65G, 103303] Funding Source: Federal RePORTER
Progressive telomere attrition or deficiency of the protective shelterin complex elicits a DNA damage response as a result of a cell's inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks. SNMIB/Apollo is a shelterin-associated protein and a member of the SMN1/PSO2 nuclease family that localizes to telomeres through its interaction with TRF2. Here, we generated SNMIB/Apollo knockout mouse embryo fibroblasts (MEFs) to probe the function of SNMIB/Apollo at mammalian telomeres. SNMIB/Apollo null MEFs exhibit an increased incidence of G2 chromatid-type fusions involving telomeres created by leading-strand DNA synthesis, reflective of a failure to protect these telomeres after DNA replication. Mutations within SNMIB/Apollo's conserved nuclease domain failed to suppress this phenotype, suggesting that its nuclease activity is required to protect leading-strand telomeres. SNMIB/Apollo(-/-)ATM(-/-) MEFs display robust telomere fusions when Trf2 is depleted, indicating that ATM is dispensable for repair of uncapped telomeres in this setting. Our data implicate the 5'-3' exonuclease function of SNM1B/Apollo in the generation of 3' single-stranded overhangs at newly replicated leading-strand telomeres to protect them from engaging the non-homologous end-joining pathway. The EMBO Journal (2010) 29, 2230-2241. doi:10.1038/emboj.2010.58; Published online 15 June 2010
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