Abstract
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.
Highlights
Chromatin structure is dynamically reorganized at multiple levels in response to DNA doublestrand breaks (DSBs)
We found that Chromodomain Helicase DNA Binding Protein 7 (CHD7) loss, similar to XRCC4 depletion, impairs clonogenic survival of VH10–SV40-immortalized fibroblasts following induction of ionizing radiation (IR)-induced DSBs (Supplementary Fig. 5m, n)
We identify the chromatin remodeler CHD7 as novel component of the DSB repair machinery and establish that a progressive reorganization of damaged chromatin through the activities of CHD7 and histone de-acetylase 1 and 2 (HDAC1/2) supports canonical NHEJ (cNHEJ) and error-free re-ligation of broken DNA ends (Fig. 7g and Supplementary Fig. 10f)
Summary
Chromatin structure is dynamically reorganized at multiple levels in response to DNA doublestrand breaks (DSBs). 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-HDAC1/2dependent cNHEJ reinforces 53BP1 assembly at the damaged chromatin and shifts DSB repair to mutagenic NHEJ, revealing a backup function of 53BP1 when cNHEJ fails. The ssDNA becomes bound by RPA, which is subsequently replaced by RAD51 in a manner dependent on BRCA1, PALB2, and BRCA2 This facilitates error-free repair of DSBs by using the undamaged sister chromatid as a template[2]. An alternative NHEJ (altNHEJ) pathway exists, which relies on the XRCC1–DNA ligase III complex and joins DSB ends in an errorprone manner using microhomology[3]
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