TY - JOUR T1 - XAB2 prevents abortive recombinational repair of replication-associated DNA double-strand breaks and its loss is synthetic lethal with RAD52 inhibition JF - bioRxiv DO - 10.1101/2020.04.10.035410 SP - 2020.04.10.035410 AU - Abhishek B. Sharma AU - Hélène Erasimus AU - Lia Pinto AU - Marie-Christine Caron AU - Katrin Neumann AU - Petr V. Nazarov AU - Barbara Klink AU - Sabrina Fritah AU - Christel C. Herold-Mende AU - Simone P. Niclou AU - Patrick Calsou AU - Jean-Yves Masson AU - Sébastien Britton AU - Eric Van Dyck Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/04/11/2020.04.10.035410.abstract N2 - Unrepaired O6-methylguanine lesions induced by the alkylating chemotherapy agent temozolomide lead to replication-associated single-ended DNA double-strand breaks (seDSBs) that are repaired predominantly through RAD51-mediated homologous recombination (HR). Here, we show that loss of the pre-mRNA splicing and DNA repair protein XAB2 leads to increased temozolomide sensitivity in glioblastoma cells, which reflects abortive HR due to Ku retention on resected seDSBs. XAB2-dependent Ku eviction also occurred at seDSBs generated by the topoisomerase I poison campthotecin and operated in parallel to an ATM-dependent pathway previously described. Although Ku retention elicited by loss of XAB2 did not prevent RAD51 focus formation, the resulting RAD51-ssDNA associations were unproductive, leading to increased engagement of non-homologous-end-joining in S/G2 and genetic instability. Overexpression of RAD51 or the single-stranded DNA annealing factor RAD52 rescued the XAB2 defects. RAD52 depletion led to severe temozolomide sensitivity, whereas a synthetic lethality interaction was observed between RAD52 and XAB2.Competing Interest StatementThe authors have declared no competing interest. ER -