Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.
Sci Rep. 2017 Oct 10;7(1):12921. doi: 10.1038/s41598-017-13036-5.
The n-terminal tail of histone H4 recruits repair proteins, including 53BP1, to DNA double-strand breaks (DSB) and undergoes dynamic acetylation during DSB repair. However, how H4 acetylation (H4Ac) recruits repair proteins and reorganizes chromatin during DNA repair is unclear. Here, we show that the bromodomain protein BRD2 is recruited to DSBs. This recruitment requires binding of BRD2's tandem bromodomains to H4Ac, which is generated at DSBs by the Tip60/KAT5 acetyltransferase. Binding of BRD2 to H4Ac protects the underlying acetylated chromatin from attack by histone deacetylases and allows acetylation to spread along the flanking chromatin. However, BRD2 recruitment is spatially restricted to a chromatin domain extending only 2 kb either side of the DSB, and BRD2 does not spread into the chromatin domains flanking the break. Instead, BRD2 facilitates recruitment of a second bromodomain protein, ZMYND8, which spreads along the flanking chromatin, but is excluded from the DSB region. This creates a spatially restricted H4Ac/BRD2 domain which reorganizes chromatin at DSBs, limits binding of the L3MBTL1 repressor and promotes 53BP1 binding, while limiting end-resection of DSBs. BRD2 therefore creates a restricted chromatin environment surrounding DSBs which facilitates DSB repair and which is framed by extensive ZMYND8 domains on the flanking chromatin.
组蛋白 H4 的 N 端尾部招募修复蛋白，包括 53BP1，到 DNA 双链断裂（DSB），并在 DSB 修复过程中经历动态乙酰化。然而，H4 乙酰化（H4Ac）如何招募修复蛋白并在 DNA 修复过程中重组染色质尚不清楚。在这里，我们表明溴结构域蛋白 BRD2 被招募到 DSB。这种招募需要 BRD2 的串联溴结构域与在 DSB 处由 Tip60/KAT5 乙酰转移酶产生的 H4Ac 结合。BRD2 与 H4Ac 的结合保护了下面的乙酰化染色质免受组蛋白去乙酰化酶的攻击，并允许乙酰化沿着侧翼染色质扩散。然而，BRD2 的募集在空间上仅限于 DSB 两侧仅延伸 2kb 的染色质域，并且 BRD2 不会扩散到断裂侧翼的染色质域中。相反，BRD2 促进了第二个溴结构域蛋白 ZMYND8 的募集，该蛋白沿着侧翼染色质扩散，但被排除在 DSB 区域之外。这创建了一个空间受限的 H4Ac/BRD2 域，该域重组 DSB 处的染色质，限制 L3MBTL1 抑制剂的结合并促进 53BP1 结合，同时限制 DSB 的末端切除。因此，BRD2 在 DSB 周围创建了一个受限的染色质环境，这有助于 DSB 修复，并且在侧翼染色质上由广泛的 ZMYND8 域构成。
