Double‐strand break repair functions of 53BP1

Abstract

Establishing the earliest events of DNA repair around a double‐strand break (DSB) is critical to our understanding of how alterations in DNA repair proteins influence human disease. Following DNA damage, a number of DSB response factors associate with chromatin containing phosphorylated histone H2AX ("γH2AX") near the break, facilitating repair via two major pathways, homologous recombination (HR) and nonhomologous end‐joining (NHEJ). In a screen for potential mediators of H2AX HR functions, we found that the DNA damage response protein 53BP1 primarily mediates not HR, but XRCC4‐dependent NHEJ. It has been proposed that 53BP1 accumulation on γH2AX chromatin requires interaction of the 53BP1 tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). To test this hypothesis, we examined DSB repair in cells genetically deleted for both of the H4K20 histone methyltransferases, Suv4‐20h1 and Suv4‐20h2. These double null cells have dramatically reduced, although not completely absent, levels of H4K20 dimethylation that are not inducible by IR. Our data suggest that H4K20me2 alone is not responsible for recruiting 53BP1 to perform its NHEJ function.