The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development.
Conserved metallo β-Lactamase and β-CASP (CPSF-Artemis-Snm1-Pso2) domain nuclease family member SNM1B/Apollo is a shelterin-associated protein that localizes to telomeres through its interaction with TRF2. To study its in vivo role, we generated a knockout of SNM1B/Apollo in a mouse model. Snm1B/Apollo homozygous null mice die at birth with developmental delay and defects in multiple organ systems. Cell proliferation defects were observed in Snm1B/Apollo mutant mouse embryonic fibroblasts (MEFs) owing to high levels of telomeric end-to-end fusions. Deficiency of the nonhomologous end-joining (NHEJ) factor Ku70, but not p53, rescued the developmental defects and lethality observed in Snm1B/Apollo mutant mice as well as the impaired proliferation of Snm1B/Apollo-deficient MEFs. These findings demonstrate that SNM1B/Apollo is required to protect telomeres against NHEJ-mediated repair, which results in genomic instability and the consequent multi-organ developmental failure. Although Snm1B/Apollo-deficient MEFs exhibited high levels of apoptosis, abrogation of p53-dependent programmed cell death did not rescue the multi-organ developmental failure in the mice.
Akhter
Shamima
S
Department of Genetics, The UT MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Lam
Yung C
YC
Chang
Sandy
S
Legerski
Randy J
RJ
D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D005090:Exodeoxyribonucleases; D005260:Female; D042822:Genomic Instability; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D034501:Telomere-Binding Proteins; D016159:Tumor Suppressor Protein p53; C551250:Dclre1b protein, mouse; D005090:Exodeoxyribonucleases