title: MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, The George Washington University, Washington, DC 20037, USA. bcmdql@gwu.edu
authors.forename: Da-Qiang
authors.initials: DQ
authors.lastname: Li
authors.forename: Sujit S
authors.initials: SS
authors.lastname: Nair
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Ohshiro
authors.forename: Anupam
authors.initials: A
authors.lastname: Kumar
authors.forename: Vasudha S
authors.initials: VS
authors.lastname: Nair
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Pakala
authors.forename: Sirigiri Divijendra Natha
authors.initials: SD
authors.lastname: Reddy
authors.forename: Rajendra P
authors.initials: RP
authors.lastname: Gajula
authors.forename: Jeyanthy
authors.initials: J
authors.lastname: Eswaran
authors.forename: L
authors.initials: L
authors.lastname: Aravind
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D042002:Chromatin Assembly and Disassembly; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense; D010766:Phosphorylation / Q000235:genetics; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C549896:MORC2 protein, human; D014157:Transcription Factors; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D000251:Adenosine Triphosphatases