We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination.
- Authors
Mateos-Gomez, Pedro A.; Gong, Fade; Nair, Nidhi; Miller, Kyle M.; Lazzerini-Denchi, Eros; Sfeir, Agnel
- Abstract
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. 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 (Polθ; 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 Polθ 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.
- Subjects
DNA repair; POLYMERASE genetics; RECOMBINANT DNA research; NUCLEOTIDE sequencing; HOMOLOGY (Biology)
- Publication
Nature, 2015, Vol 518, Issue 7538, p254
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature14157