RAD51 protein repairs highly toxic DNA damage via homologous recombination and protects replication forks from nucleolytic degradation. Recently, RAD51 mutations were identified in several tumor types. However, the mechanism of how these mutations contribute to tumorigenesis remains elusive. This work reports a biochemical characterization of RAD51 S121Y mutation found in uterine carcinosarcoma. Intriguingly, while RAD51 S121Y is recombination proficient, reconstitution of fork protection using synthetic DNA substrates revealed that RAD51 S121Y is unable to efficiently prevent MRE11 exonuclease-mediated DNA degradation. All together these results elucidate a mechanism by which can RAD51 mutations promote tumorigenesis.


Karina Movsesjan