MORC2 regulates DNA damage response through a PARP1-dependent pathway.
Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling enzyme with an emerging role in DNA damage response (DDR), but the underlying mechanism remains largely unknown. Here, we show that poly(ADP-ribose) polymerase 1 (PARP1), a key chromatin-associated enzyme responsible for the synthesis of poly(ADP-ribose) (PAR) polymers ... in mammalian cells, interacts with and PARylates MORC2 at two residues within its conserved CW-type zinc finger domain. Following DNA damage, PARP1 recruits MORC2 to DNA damage sites and catalyzes MORC2 PARylation, which stimulates its ATPase and chromatin remodeling activities. Mutation of PARylation residues in MORC2 results in reduced cell survival after DNA damage. MORC2, in turn, stabilizes PARP1 through enhancing acetyltransferase NAT10-mediated acetylation of PARP1 at lysine 949, which blocks its ubiquitination at the same residue and subsequent degradation by E3 ubiquitin ligase CHFR. Consequently, depletion of MORC2 or expression of an acetylation-defective PARP1 mutant impairs DNA damage-induced PAR production and PAR-dependent recruitment of DNA repair proteins to DNA lesions, leading to enhanced sensitivity to genotoxic stress. Collectively, these findings uncover a previously unrecognized mechanistic link between MORC2 and PARP1 in the regulation of cellular response to DNA damage.
Mesh Terms:
Acetylation, Cell Cycle Proteins, Cell Line, Tumor, Chromatin, Chromatin Assembly and Disassembly, DNA Damage, DNA Repair, HEK293 Cells, Humans, Mutation, N-Terminal Acetyltransferase E, Neoplasm Proteins, Phthalazines, Piperazines, Poly (ADP-Ribose) Polymerase-1, Poly Adenosine Diphosphate Ribose, Poly(ADP-ribose) Polymerase Inhibitors, Poly-ADP-Ribose Binding Proteins, Protein Processing, Post-Translational, Proteolysis, Signal Transduction, Transcription Factors, Ubiquitin-Protein Ligases, Ubiquitination
Acetylation, Cell Cycle Proteins, Cell Line, Tumor, Chromatin, Chromatin Assembly and Disassembly, DNA Damage, DNA Repair, HEK293 Cells, Humans, Mutation, N-Terminal Acetyltransferase E, Neoplasm Proteins, Phthalazines, Piperazines, Poly (ADP-Ribose) Polymerase-1, Poly Adenosine Diphosphate Ribose, Poly(ADP-ribose) Polymerase Inhibitors, Poly-ADP-Ribose Binding Proteins, Protein Processing, Post-Translational, Proteolysis, Signal Transduction, Transcription Factors, Ubiquitin-Protein Ligases, Ubiquitination
Nucleic Acids Res.
Date: Dec. 19, 2018
PubMed ID: 31616951
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