Dimerization of MORC2 through its C-terminal coiled-coil domain enhances chromatin dynamics and promotes DNA repair

Abstract

Decondesation of the highly compacted chromatin architecture is essential for efficient DNA repair, but how this is achieved remains largely unknown. Here, we report that microrchidia family CW-type zinc finger protein 2 (MORC2), a newly identified ATPase-dependent chromatin remodeling enzyme, is required for nucleosome destabilization after DNA damage through loosening the histone-DNA interaction. Depletion of MORC2 attenuates phosphorylated histone H2AX (γH2AX) focal formation, compromises the recruitment of DNA repair proteins, BRCA1, 53BP1, and Rad51, to sites of DNA damage, and consequently reduces cell survival following treatment with DNA-damaging chemotherapeutic drug camptothecin (CPT). Furthermore, we demonstrate that MORC2 can form a homodimer through its C-terminal coiled-coil (CC) domain, a process that is enhanced in response to CPT-induced DNA damage. Deletion of the C-terminal CC domain in MORC2 disrupts its homodimer formation and impairs its ability to destabilize histone-DNA interaction after DNA damage. Consistently, expression of dimerization-defective MORC2 mutant results in impaired the recruitment of DNA repair proteins to damaged chromatin and decreased cell survival after CPT treatment. Together, these findings uncover a new mechanism for MORC2 in modulating chromatin dynamics and DDR signaling through its c-terminal dimerization.

The chromatin modifier MORC2 affects glucose metabolism by regulating the expression of lactate dehydrogenase A through a feed forward loop with c‐Myc

“…LDH activity was expressed as 'n moles of NADH formedÁmin À1 Álg À1 of protein'. *P < 0.05, **P < 0.01, and ***P < 0.001. structure either by protein-DNA or protein-protein interaction [15,[21][22][23]29]. Here, we have found that MORC2 coregulates LDHA expression by interacting with c-Myc (Figs S10 and S11).…”

“…MORC2 is not a transcription factor, but it can regulate the gene transcription by altering the chromatin structure either by protein–DNA or protein–protein interaction [15,21–23,29]. Here, we have found that MORC2 coregulates LDHA expression by interacting with c‐Myc (Figs S10 and S11).…”

“…MORC2 has recently been identified as a chromatin modifier besides its significant role in DNA repair, lipogenesis, and cancer metastasis [15,[21][22][23]29]. MORC2 was found to be upregulated in many cancers and shown to have profound effect on tumorigenesis and cancer progression [16,17,30,31].…”

Circular RNA circDNM3OS Functions as a miR-145-5p Sponge to Accelerate Cholangiocarcinoma Growth and Glutamine Metabolism by Upregulating MORC2

“…MORC2 is a member of the MORC ATPase superfamily, and it plays vital roles in diverse biological processes, such as lipogenesis, DNA damage repair, and chromatin remodeling. 31–33 MORC2 had been uncovered as an oncogene in liver cancer. 34 Moreover, miR-186-5p targeted MORC2 to curb metastasis and growth of CCA cells.…”

Characterization of Genotype–Phenotype Correlation With MORC2 Mutated Axonal Charcot–Marie–Tooth Disease in a Cohort of Chinese Patients

“…MORC2 is a 1032-amino acid (AA) protein predicted to contain several functional domains. The Nterminal catalytically active ATPase module is composed of Gyrase B, Hsp90, histidine kinase, and MutL (GHKL) and S5-fold domains (AA residues 1-469), which has been mechanistically linked to gene transcription and DNA repair by remodeling chromatin [3][4].The CW-type zinc nger domain(AA residues 490-544) participates in chromatin regulation through the recognition of epigenetic signals [4].The C-terminal chromo-like domain(AA residues 795-850) is commonly found in eukaryotic chromatin proteins and can recognize methylated peptides in histones and nonhistone proteins [25].The coiled-coil domains is suggested to be an important structural determinant for protein assembly and molecular recognition [25]. It is interesting to note that the different mutations causing distinct changes in biochemical properties (Table 3) [6], which may be helpful to understand MORC2 mutations cause the complex range of clinical symptoms.…”