Accession Number : AD1047497


Title :   Deciphering the Role of Alternative Non-Homologous End Joining (Alt-NHEJ) DNA Repair in Breast Cancer


Descriptive Note : Technical Report,15 Sep 2014,14 Sep 2017


Corporate Author : New York University School of Medicine New York United States


Personal Author(s) : Mateos-Gomez,Pedro A


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1047497.pdf


Report Date : 01 Dec 2017


Pagination or Media Count : 84


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 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 Po1Q indicated that the helicase and polymerase domains are relevant for its activity, having an impact in translocation frequency, RAD51 foci formation or survival of BRCA1 depleted cells. Finally, PolQ though its helicase domain and RPA interplay at DSB to promote A-NHEJ or HR respectively.


Descriptors :   breast cancer , DNA , repair , lesions , mutations , neoplasms , cells(biology) , GENOMIC INSTABILITY , cell line


Subject Categories : Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE