SNMIB/Apollo protects leading-strand telomeres against NHEJ-mediated repair.
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.
Lam
Yung C
YC
Department of Genetics Unit 1010, The U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
Akhter
Shamima
S
Gu
Peili
P
Ye
Jing
J
Poulet
Anaïs
A
Giraud-Panis
Marie-Josèphe
MJ
Bailey
Susan M
SM
Gilson
Eric
E
Legerski
Randy J
RJ
Chang
Sandy
S
D000626:Aminopeptidases / Q000378:metabolism; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002875:Chromosomes / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005090:Exodeoxyribonucleases; D005347:Fibroblasts / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D057057:Serine Proteases / Q000378:metabolism; D000089804:Shelterin Complex; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000091346:Tripeptidyl-Peptidase 1; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C507326:POT1 protein, mouse; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D000091346:Tripeptidyl-Peptidase 1; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C551250:Dclre1b protein, mouse; D005090:Exodeoxyribonucleases; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases