Inhibition of 53BP1: Potential for Restoring Homologous Recombination In Ovarian Cancer Cells
Abstract
In this Pilot Award, we explore at the molecular level how the relocation of DNA damage response (DDR) protein 53BP1 to chromatin harboring DNA double-strand breaks (DSBs) can be negatively regulated. 53BP1 is a natural inhibitor of homologous recombination (HR), a DNA repair pathway that is often inhibited in ovarian cancer cells. Therefore, by preventing the chromatin recruitment of 53BP1 one could in principle activate HR. Our idea is that by understanding how 53BP1recruitment is regulated we could design ways to block 53BP1 chromatin recruitment in ovarian cancer cells, and by this means correct the HR defect and prevent ovarian tumor formation. We have three aims. For this first year of funding, our work for Aim 1 has revealed how a DDR protein can block the 53BP1-binding surface on the nucleosome, the smallest subunit of chromatin. Our studies for Aim 2 show how a regulatory protein blocks the chromatin-binding domain of 53BP1. For Aim 3, our data reveal how small synthetic organic chemicals trigger the dimerization of 53BP1 and thereby mask the chromatin-binding surface of 53BP1. The significance of our combined work is that it shows how 53BP1 chromatin recruitment can be inhibited by blocking the 53BP1-binding site in chromatin (Aim 1), or by blocking the chromatin-binding domain of 53BP1 (Aims 2 and 3). In future studies, we will probe the effectiveness of 53BP1 inhibition in correcting HR defects in ovarian cancer cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2017
- Accession Number
- AD1050229
Entities
People
- Maria V. Botuyan
Organizations
- Mayo Clinic