Deciphering the Role of Alternative nonhomologous End Joining (Alt NHEJ) DNA Repair in Breast Cancer
Technical Report,15 Sep 2015,14 Sep 2016
New York University School of Medicine New York United States
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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. We showed that Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq results in increased rates of homology-directed repair HR, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we showed that depletion of PolQ had 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 tumors carrying mutations in homology-directed repair genes. Here we report that PolQ inhibition can be used to increase the efficiency of CRISPR targeting. Function-Structure analysis of PolQ indicated that the helicase and polymerase domains are relevant for its activity, in contrast deletion of the RAD51 interaction motif did no have an impact in translocation frequency, RAD51 foci formation or survival of BRCA1 depleted cells. Finally, PolQ and RPA interplay at DSB to promote A-NHEJ or HR respectively.
- Medicine and Medical Research