Appropriate DNA end synapsis, regulated by core components of the synaptic complex including KU70KU80, LIG4, XRCC4, and XLF, is central to non -homologous end joining (NHEJ) repair of chromatinized DNA double -strand breaks (DSBs). However, it remains enigmatic whether chromatin modifications can influence the formation of NHEJ synaptic complex at DNA ends, and if so, how this is achieved. Here, we report that the mitotic deacetylase complex (MiDAC) serves as a key regulator of DNA end synapsis during NHEJ repair in mammalian cells. Mechanistically, MiDAC removes combinatorial acetyl marks on histone H2A (H2AK5acK9ac) around DSB-proximal chromatin, suppressing hyperaccumulation of bromodomain-containing protein BRD4 that would otherwise undergo liquid -liquid phase separation with KU80 and prevent the proper installation of LIG4-XRCC4-XLF onto DSB ends. This study provides mechanistic insight into the control of NHEJ synaptic complex assembly by a specific chromatin signature and highlights the critical role of H2A hypoacetylation in restraining unscheduled compartmentalization of DNA repair machinery.
[1]Tianjin Med Univ, Key Lab Breast Canc Prevent & Therapy, State Key Lab Expt Hematol, Minist Educ,Haihe Lab Cell Ecosyst,Key Lab Immune, Tianjin, Peoples R China.
[2]Capital Med Univ, Core Facil Ctr, Beijing, Peoples R China.
[3]Nankai Univ, Coll Pharm, State Key Lab Med Chem Biol, Tianjin, Peoples R China.
[4]Chinese Acad Sci, Ctr Excellence Mol Cell Sci, State Key Lab Mol Biol, Shanghai, Peoples R China.
[5]Peking Univ, Sch Pharmaceut Sci, Dept Mol & Cellular Pharmacol, State Key Lab Nat & Biomimet Drugs, Beijing, Peoples R China.
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