Journal
NATURE
Volume 518, Issue 7538, Pages 254-U285Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature14157
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Funding
- Breast Cancer Alliance
- V-foundation
- Department of Defense Breast Cancer Research Program [BC134020]
- Pew-Stewart Scholars Award
- Pew Scholars Award
- Novartis Advanced Discovery Institute
- National Institutes of Health (NIH) [AG038677]
- Helen L. and Martin S. Kimmel Center for Stem Cell Biology
- University of Texas at Austin
- Cancer Prevention Research Institute of Texas (CPRIT) [R116]
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The alternative non-homologous end-joining (NHEJ) machinery facilitates several genomic rearrangements, some of which can lead to cellular transformation. This error-prone repair pathway is triggered upon telomere de-protection to promote the formation of deleterious chromosome end-to-end fusions(1-3). Using next-generation sequencing technology, here we show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres. Investigating the enzymatic activity responsible for the random insertions enabled us to identify polymerase theta (Pol theta; encoded by Polq in mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq in mice results in increased rates of homology-directed repair, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we show that depletion of Pol theta has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes.
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