| First Author | Mateos-Gomez PA | Year | 2015 |
| Journal | Nature | Volume | 518 |
| Issue | 7538 | Pages | 254-7 |
| PubMed ID | 25642960 | Mgi Jnum | J:219558 |
| Mgi Id | MGI:5621198 | Doi | 10.1038/nature14157 |
| Citation | Mateos-Gomez PA, et al. (2015) Mammalian polymerase theta promotes alternative NHEJ and suppresses recombination. Nature 518(7538):254-7 |
| abstractText | 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 (Poltheta; 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 Poltheta 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. |
