Abstract 2482: Bat3 facilitates histone H3 lysine 79 dimethylation by DOT1L to promote ionizing radiation-induced 53BP1 foci formation during G1- and G2-phases of the cell cycle

DOT1L is a unique histone methyltransferase involved in normal cellular metabolism and in the initiation of certain leukemias. DOT1L specifically methylates histone H3 at K79, promoting the interaction of H3 with various binding partners. 53BP1, a component of the DNA damage response machinery, has been shown to interact with H3 K79-diMe following exposure to ionizing radiation; however, it remains unclear if this modification is required for 53BP1 foci formation as 53BP1 interacts with histone H4 K20-diMe with a much higher efficiency. Here, we clarify the role of H3 K79-diMe by demonstrating that this modification contributes to IR-induced 53BP1 foci formation during G1- and G2-phases of the cell cycle, but is negligible during S-phase. Further, we describe an essential role for HLA-B-associated transcript 3 (Bat3) in regulating this process. Bat3 co-localizes with DOT1L at histone H3, and Bat3 knockdown results in decreased DOT1L-H3 interaction and H3 K79-diMe, leading to a reduction in IR-induced 53BP1 foci formation. Bat3-depleted cells also exhibit defects in DNA repair and increased sensitivity to IR. We demonstrate that a conserved ubiquitin-like motif of Bat3 and a conserved DOT1L ubiquitin interacting motif are required for DOT1L-Bat3 interaction, which promotes efficient H3 K79-diMe and IR-induced 53BP1 foci formation. Taken together, our data identify a novel role for Bat3 in regulating DOT1L function.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2482. doi:10.1158/1538-7445.AM2011-2482

Duke Scholars

Author Xiao-Fan Wang Pharmacology & Cancer Biology