Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
Nat Commun. 2020 Nov 13;11(1):5775. doi: 10.1038/s41467-020-19502-5.
Chromatin structure is dynamically reorganized at multiple levels in response to DNA double-strand breaks (DSBs). Yet, how the different steps of chromatin reorganization are coordinated in space and time to differentially regulate DNA repair pathways is insufficiently understood. Here, we identify the Chromodomain Helicase DNA Binding Protein 7 (CHD7), which is frequently mutated in CHARGE syndrome, as an integral component of the non-homologous end-joining (NHEJ) DSB repair pathway. Upon recruitment via PARP1-triggered chromatin remodeling, CHD7 stimulates further chromatin relaxation around DNA break sites and brings in HDAC1/2 for localized chromatin de-acetylation. This counteracts the CHD7-induced chromatin expansion, thereby ensuring temporally and spatially controlled 'chromatin breathing' upon DNA damage, which we demonstrate fosters efficient and accurate DSB repair by controlling Ku and LIG4/XRCC4 activities. Loss of CHD7-HDAC1/2-dependent cNHEJ reinforces 53BP1 assembly at the damaged chromatin and shifts DSB repair to mutagenic NHEJ, revealing a backup function of 53BP1 when cNHEJ fails.
染色质结构在应对 DNA 双链断裂 (DSB) 时会在多个层次上动态重组。然而，不同的染色质重排步骤如何在空间和时间上协调，以差异化调节 DNA 修复途径，还了解不足。在这里，我们鉴定出 Chromodomain Helicase DNA Binding Protein 7 (CHD7)，它在 CHARGE 综合征中经常发生突变，是非同源末端连接 (NHEJ) DSB 修复途径的一个组成部分。通过 PARP1 触发的染色质重塑募集后，CHD7 刺激 DNA 断裂部位周围的进一步染色质松弛，并将 HDAC1/2 带入局部染色质去乙酰化。这抵消了 CHD7 诱导的染色质扩张，从而确保了 DNA 损伤时时空受控的“染色质呼吸”，我们证明这通过控制 Ku 和 LIG4/XRCC4 活性促进了高效和准确的 DSB 修复。CHD7-HDAC1/2 依赖性 cNHEJ 的缺失增强了受损染色质上 53BP1 的组装，并将 DSB 修复转移到致突变的 NHEJ，揭示了当 cNHEJ 失败时 53BP1 的备份功能。
