Homologous recombination-mediated DNA repair is essential for maintaining genome integrity. It is a multi-step process that involves resection of DNA ends, strand invasion, DNA synthesis and/or DNA end ligation, and finally, the processing of recombination intermediates such as Holliday junctions or other joint molecules. Mutations in genes required for homologous recombination are associated with a range of cancer predisposition syndromes, defining a pathway for genomic instability-induced oncogenesis. Paradoxically, the ability of many cancers to utilize homologous recombination is crucial for them to cope with oncogene-induced replication stress, providing opportunity for the use of inhibitors of homologous recombination in cancer treatment. Despite the relevance, the molecular mechanisms for controlling homologous recombination are not yet fully elucidated, limiting our ability to properly explore the concept of homologous recombination inhibition in cancer therapy. Here I will present our current work focused on dissecting how kinases control homologous recombination in yeast and in humans. Our findings define the centrality of the ATR kinase for proper cell cycle-dependent control of homologous recombination. Results also establish the role of the Dpb11/TOPBP1 scaffold as a “reader” of DNA damage-induced phosphorylation and a coordinator of recombination factor recruitment for the control of DNA end resection and subsequent steps in homologous recombination-mediated repair. Finally, I will discuss how our findings are providing rationale for the use of ATR inhibitors for the controlled modulation of homologous recombination capacity and selective killing of homologous recombination-proficient cancers.

Phosphorylation control of homologous recombination

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.