SNMIB/Apollo protects leading-strand telomeres against NHEJ-mediated repair

EMBO J. 2010 Jul 7;29(13):2230-41. doi: 10.1038/emboj.2010.58. Epub 2010 Jun 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminopeptidases / metabolism
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Chromosomes / metabolism
  • DNA Damage
  • DNA Repair*
  • DNA-Binding Proteins / metabolism
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism
  • Embryo, Mammalian / cytology
  • Exodeoxyribonucleases
  • Fibroblasts / metabolism*
  • Mice
  • Mice, Knockout
  • Protein Serine-Threonine Kinases / metabolism
  • Serine Proteases / metabolism
  • Shelterin Complex
  • Telomere / metabolism*
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism*
  • Tripeptidyl-Peptidase 1
  • Tumor Suppressor Proteins / metabolism


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • POT1 protein, mouse
  • Shelterin Complex
  • Telomere-Binding Proteins
  • Tripeptidyl-Peptidase 1
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases
  • Dclre1b protein, mouse
  • Exodeoxyribonucleases
  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases