PT  - JOURNAL ARTICLE
AU  - Josée Guirouilh-Barbat
AU  - Wei Yu
AU  - Loelia Babin
AU  - Elisa Yaniz Galende
AU  - Tatiana Popova
AU  - Ayeong So
AU  - Chloé Lescale
AU  - Marc-Henri Stern
AU  - Erika Brunet
AU  - Ludovic Deriano
AU  - Bernard S. Lopez
TI  - RAD51 promotes non-homologous genetic rearrangements that are prevented by 53BP1
AID  - 10.1101/768788
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 768788
4099  - http://biorxiv.org/content/early/2019/09/14/768788.short
4100  - http://biorxiv.org/content/early/2019/09/14/768788.full
AB  - Homologous recombination (HR), which requires long sequence homologies, is considered a high fidelity mechanism, preserving genome stability. In contrast, we show here that the central HR players RAD51 or BRCA2, promote genetic instability, fostering translocations and capture of ectopic chromosomal sequences when joining distant DNA breaks. Surprisingly, these events do not involve sequence homologies. Moreover, our data reveal that 53BP1 protects against RAD51-mediated non-homologous genetic rearrangements. Finally, analysis of a large panel of breast tumors revealed that BRCA2 proficiency is associated with increased frequency of capture of non-homologous sequences at junctions of structural variants (translocations, duplications, inversions, deletions). These data reveal that HR proteins (RAD51, BRCA2) possess the intrinsic capacity to generate genetic instability through sequence homology-independent processes, and that 53BP1 protects against it. We propose that BRCA2/RAD51-mediated genome instability occurs in the course of sequence homology search for HR.