2018 Recipient Maria Victoria Botuyan, PhD

Maria Victoria Botuyan, PhD

Probing the Antagonistic Roles of 53BP1 and RAD18 in HR DNA Repair

Project Summary

Our DNA is constantly being damaged by, for example, UV light, ionizing radiations, or even normal biochemical processes in our body. The damage can take many forms, the most serious being a break in both strands of the DNA (a double-strand break or DSB). We have evolved ways of fixing DNA damage, with many proteins inside our cells relocating to the damaged site and participating in the repair processes. Most of the time repair is successful, but sometimes it is not and this can lead to cancer. Inside our cells, DNA is in a compacted form as part of the so-called chromatin. When there is a DSB, the site of damage is marked by the attachment to chromatin of a chemical signal called ubiquitin. In this application, we want to study how two proteins, named 53BP1 and RAD18, work together in one DSB repair process called homologous recombination or HR DNA repair. 53BP1 inhibits HR repair while RAD18 activates HR repair. A delicate balance between the relocations of 53BP1 and RAD18 to DNA damage sites is needed for accurate HR repair. We will investigate how 53BP1 and RAD18 relocate to DSBs in chromatin, and therefore how this balance is achieved and how normal HR repair takes place. From our preliminary studies, we have evidence that when a DSB occurs, 53BP1 and RAD18 recognize and compete for the same chromatin-ubiquitin surface. These studies are important because defective HR repair is linked to cancer, notably ovarian cancer. The knowledge we will gain about the involvement of 53BP1 and RAD18 in HR repair will provide a solid basis to help us devise new therapies for ovarian cancer. Since 53BP1 naturally inactivates HR repair, one could imagine ways to inactivate 53BP1 and hence reactivate HR when HR is defective like in cancer. Alternatively, since RAD18 naturally activates HR repair, one could devise ways to inactivate RAD18 and thus inactivate HR. Paradoxically, inactivating HR DNA repair in cancer cells could make them more sensitive to cell killing agents like PARP inhibitors, which have already shown great promise in treating ovarian cancer. With RAD18 inhibitors, we could possibly make PARP inhibitors more effective in killing ovarian cancer cells.

Bio

Dr. Botuyan received her B.S. in Chemistry from the University of the Philippines and Ph.D. in Chemistry from Purdue University. She did her postdoctoral training at the Scripps Research Institute, the Beckman Research Institute of the City of Hope, the University of Toronto, and the Mayo Clinic. She is currently a Research Scientist and an Assistant Professor at the Mayo Clinic in Rochester, MN. Dr. Botuyan is interested in understanding the molecular basis of the DNA damage response (DDR), and how defective DDR, which can lead to cancer, could be manipulated to treat the disease. As a trained biochemist and structural biologist, she has characterized the 3D structures and interactions of several DDR protein domain complexes, with some of the interactions directed by serine phosphorylation, lysine methylation, and lysine ubiquitylation. Dr. Botuyan’s current work focuses on elucidating the molecular mechanism for the antagonistic actions of DDR proteins 53BP1 and RAD18 in the homologous recombination repair of DNA double-strand breaks, and how the inhibition of these proteins by small molecules might be exploited to develop new therapeutics for ovarian cancer. Dr. Botuyan is the recipient of a US Department of Defense Ovarian Cancer Research Program award.