The DNTTIP1-PARP1 interaction orchestrates MiDAC recruitment and activity for NHEJ-mediated genome stability.

The Mitotic Deacetylase Complex (MiDAC) plays a crucial role in the DNA damage response (DDR), yet the mechanism of its recruitment to double-strand breaks (DSBs) remains poorly unclear. In this study, we identify Poly(ADP-ribose) polymerase 1 (PARP1) as the key factor that directs MiDAC to DSB-proximal chromatin. We demonstrate that this process depends on the physical presence of PARP1, but not its poly(ADP-ribosyl)ation (PARylation) activity. Specifically, the dimerization domain of the MiDAC subunit DNTTIP1 interacts directly with PARP1. Disrupting this interaction prevents MiDAC recruitment and impairs the deacetylation of histone H2A at lysine 5 and 9 (H2AK5ac/K9ac) at damage sites. This leads to genome instability, characterized by an increase in γH2AX foci, accumulation of DNA damage, and chromosomal breaks. The PARP1-DNTTIP1 interaction is mechanistically essential for the assembly of the non-homologous end joining (NHEJ) synaptic complex, as evidenced by a defective KU80-LIG4 interaction and impaired NHEJ efficiency when this interaction is disrupted. Consequently, this interaction is critical for physiological processes that rely on NHEJ, such as immunoglobulin class switch recombination (CSR) in B cells. Our findings establish the PARP1-DNTTIP1 axis as a critical PARylation-independent regulator of MiDAC, linking the sensing of early DNA damage to the subsequent remodeling of chromatin and the efficient repair of DSBs.