DNA Double-Strand Break Movement in Heterochromatin Depends on theDrosophilaHistone Acetyltransferase Gcn5

Abstract

AbstractCells employ diverse strategies to repair double-strand breaks (DSBs), a dangerous form of DNA damage that threatens genome integrity. Eukaryotic nuclei consist of different chromatin environments, each displaying distinct molecular and biophysical properties that can significantly influence the DSB repair process. Specifically, DSBs arising in the compact and silenced heterochromatin domains have been found to move to the heterochromatin periphery in mouse andDrosophilato prevent aberrant recombination events. However, it is poorly understood how chromatin components, such as histone post-translational modifications, contribute to these DSB movements within heterochromatin. Using cultured cells and anin vivosingle-DSB system inDrosophila, we identify that histone H3 lysine 9 acetylation (H3K9ac) is enriched at DSBs in heterochromatin but not euchromatin. We find that this enrichment is mediated by the histone acetyltransferase Gcn5, which rapidly localizes to heterochromatic DSBs. Moreover, we demonstrate that in the absence of Gcn5, heterochromatic DSBs display impaired recruitment of the SUMO E3 ligase Nse2/Qjt and fail to relocate to the heterochromatin periphery to complete repair. In summary, our results reveal a previously unidentified role for Gcn5 and H3K9ac in heterochromatin DSB repair and underscore the importance of differential chromatin responses at hetero- and eu-chromatic DSBs to promote safe repair.