Abstract
Because of their defect in homologous recombination, BRCA1-deficient cancers use polymerase theta (POLQ) microhomology-mediated end joining (MMEJ) to repair stressed replication forks. We found that BRCA1-deficient cells repress microRNA (miR) 4485-3p, and reconstituting its expression caused BRCA1-deficient cells to die. In our investigation of the mechanism of this synthetic lethality, we found that miR-4485-3p suppresses RPRD1B expression. Depleting RPRD1B led to selective BRCA1-deficient cell death, decreased MMEJ, and reduced replication fork repair after replication stress. RPRD1B promotes the recruitment of the MMEJ components 53BP1, PARP1, and POLQ to the stressed replication fork. However, RPRD1B does not have a canonical DNA-binding domain, and our search for the mechanism of its recruitment to stressed replication forks discovered that this is mediated by RECQL5 and ubiquitinated (Ub) PCNA. Thus, our results unveil an essential signaling cascade at the stressed replication fork in BRCA1-deficient cancer cells, in which Ub PCNA recruits RECQL5, which recruits RPRD1B to mediate the assembly of the MMEJ repair apparatus. These data suggest that this repair scaffold may be targeted in the development of a novel synthetic therapy for BRCA1-deficient cancers.
Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to the understanding of its causes, and accelerate the translation of knowledge into novel therapies. Through the discovery, development, and dissemination of new scientific knowledge, Greehey CCRI strives to have a national and global impact on childhood cancer. Our mission consists of three key areas: research, clinical, and education.
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