ATPase MORC2

Definition:

Essential for epigenetic silencing by the HUSH (human silencing hub) complex. Recruited by HUSH to target site in heterochromatin, the ATPase activity and homodimerization are critical for HUSH-mediated silencing. Represses germ cell-related genes and L1 retrotransposons in collaboration with SETDB1 and the HUSH complex, the silencing is dependent of repressive epigenetic modifications, such as H3K9me3 mark. Silencing events often occur within introns of transcriptionally active genes, and lead to the down-regulation of host gene expression. During DNA damage response, regulates chromatin remodeling through ATP hydrolysis. Upon DNA damage, is phosphorylated by PAK1, both colocalize to chromatin and induce H2AX expression. ATPase activity is required and dependent of phosphorylation by PAK1 and presence of DNA. Recruits histone deacetylases, such as HDAC4, to promoter regions, causing local histone H3 deacetylation and transcriptional repression of genes such as CA9. Exhibits a cytosolic function in lipogenesis, adipogenic differentiation, and lipid homeostasis by increasing the activity of ACLY, possibly preventing its dephosphorylation.

References:

[1]. Beatriz Sánchez-Solana, et al. Cytosolic functions of MORC2 in lipogenesis and adipogenesis. Biochim Biophys Acta. 2014 Feb;1843(2):316-26. [Content Brief]

[2]. Nian Liu, et al. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Nature. 2018 Jan 11;553(7687):228-232. [Content Brief]

[3]. Iva A Tchasovnikarova, et al. Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2. Nat Genet. 2017 Jul;49(7):1035-1044. [Content Brief]

[4]. Yangguang Shao, et al. Involvement of histone deacetylation in MORC2-mediated down-regulation of carbonic anhydrase IX. Nucleic Acids Res. 2010 May;38(9):2813-24. [Content Brief]

[5]. Gui-Ling Wang, et al. Identification and expression analysis of a novel CW-type zinc finger protein MORC2 in cancer cells. Anat Rec (Hoboken). 2010 Jun;293(6):1002-9. [Content Brief]

[6]. Da-Qiang Li, et al. MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response. Cell Rep. 2012 Dec 27;2(6):1657-69. [Content Brief]

[7]. Christopher H Douse, et al. Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms. Nat Commun. 2018 Feb 13;9(1):651. [Content Brief]

[8]. Maria J Guillen Sacoto, et al. De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism. Am J Hum Genet. 2020 Aug 6;107(2):352-363. [Content Brief]

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