Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1047-1056 |
Number of pages | 10 |
Journal | Aging Cell |
Volume | 9 |
Issue number | 6 |
DOIs | |
State | Published - Dec 2010 |
Keywords
- Chromosome instability
- Ku
- Mouse model
- Nonhomologous end-joining
- SNM1B/Apollo
- Telomeres
ASJC Scopus subject areas
- Aging
- Cell Biology
MD Anderson CCSG core facilities
- Genetically Engineered Mouse Facility