MORC2 Signaling Integrates Phosphorylation-Dependent, ATPase-Coupled Chromatin Remodeling during the DNA Damage Response

Chromatin dynamics play a central role in maintaining genome integrity, but how this is achieved remains largely unknown. Here, we report that microrchidia CW-type zinc finger 2 (MORC2), an uncharacterized protein with a derived PHD finger domain and a conserved GHKL-type ATPase module, is a physiological substrate of p21-activated kinase 1 (PAK1), an important integrator of extracellular signals and nuclear processes. Following DNA damage, MORC2 is phosphorylated on serine 739 in a PAK1-dependent manner, and phosphorylated MORC2 regulates its DNA-dependent ATPase activity to facilitate chromatin remodeling. Moreover, MORC2 associates with chromatin and promotes gamma-H2AX induction in a PAK1 phosphorylation-dependent manner. Consequently, cells expressing MORC2-S739A mutation displayed a reduction in DNA repair efficiency and were hypersensitive to DNA-damaging agent. These findings suggest that the PAK1-MORC2 axis is critical for orchestrating the interplay between chromatin dynamics and the maintenance of genomic integrity through sequentially integrating multiple essential enzymatic processes. [Display omitted] ► MORC2 is a DNA damage-responsive phosphoprotein activated by PAK1 kinase ► MORC2 regulates phosphorylation-coupled, ATPase-dependent chromatin remodeling ► MORC2 facilitates gamma-H2AX induction independently of PIKK kinases ► MORC2 promotes DSB repair in a PAK1 phosphorylation-dependent manner Chromatin dynamics play a critical role in maintaining genome integrity. Li, Kumar, and colleagues demonstrate that microrchidia CW-type zinc finger 2 (MORC2) is a chromatin remodeling protein and a modifier of radiosensitivity. MORC2 facilitates ATPase-coupled chromatin relaxation to govern DNA double-strand break signaling in a p21-activated kinase 1 (PAK1) phosphorylation-dependent manner. These findings establish that the PAK1-MORC2 axis is emerging as a central mediator of the cellular response to DNA damage through sequentially integrating multiple essential enzymatic processes.