MORC2

Official Full Name

MORC family CW-type zinc finger 2

Organism

Homo sapiens

GeneID

22880

Background

This gene encodes a member of the Microrchidia (MORC) protein superfamily. The encoded protein is known to regulate the condensation of heterochromatin in response to DNA damage and play a role in repressing transcription. The protein has been found to regulate the activity of ATP citrate lyase via specific interaction with this enzyme in the cytosol of lipogenic breast cancer cells. The protein also plays a role in lipogenesis and adipocyte differentiation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2016]

Synonyms

ZCW3; CMT2Z; DIGFAN; ZCWCC1;

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Detailed Information

MORC (microrchidia) is a highly conserved nuclear protein superfamily with MORC family members in humans, mice, nematodes, plants (such as Arabidopsis) and myxobacteria. MORC2 (also known as ZCWCC1, ZCW3, KIAA0852 or AC004542.C22.1) is a ubiquitously expressed protein involved in chromatin remodeling, promoting DNA double strand break (DSB) repair and cell survival. In response to DNA damage, MORC2 is phosphorylated by p21-activated kinase 1 (PAK1) and regulates chromatin remodeling through its DNA-dependent ATPase activity. The cytoplasmic MORC2 also exerts a role unrelated to transcriptional regulation: when preadipocytes differentiate into adipocytes, MORC2 expression is up-regulated and interacts with ATP-citrate lyase (ACLY), which promotes ATP-ACLY Activated to promote adipogenesis and adipogenic differentiation.

MORC2 also forms a protein complex with histone deacetylase 4 (HDAC4), which exerts a negative transcriptional regulation through epigenetic means. The first downstream gene, CAIX, which is directly regulated by MORC2, has been identified. A small amount of MORC2 expressed in the cytoplasm also exerts an effect unrelated to the function of regulating transcription: when the preadipocytes differentiate into adipocytes, the MORC2 content in the cytoplasm rises and interacts with ATP-citrate lyase, Promoting the activation of the latter. Studies have shown that after overexpression of MORC2, p53 protein levels in L02 hepatocytes decreased before and after induction of steatosis. qRT-PCR and Westernblot confirmed p53 overexpression was successful, and overexpression of p53 partially relieved MORC2 from alleviating L02 hepatic steatosis effect.

Figure 1. MORC2 and ACLY interact in the cytosol of MCF-7 cells. (Sánchez-Solana, et al. 2014)

MORC2 and Tumor

The C-terminus of MORC2 contains a nuclear localization signal and a proline-rich domain that is critical for the transcriptional repression of MORC2 in tumor cells. The study used gene expression profiling to analyze the gene expression profile of cancer tissues in patients with triple-negative breast cancer and found that MORC2 can predict the risk of recurrence of triple-negative breast cancer. In 2014, Tuupanen et al. reported that MORC2 is one of the candidate oncogenes for mutations in microsatellite unstable colorectal cancer. MORC2 is capable of exerting negative transcriptional regulation through epigenetic means. In gastric cancer cells, MORC2 is able to recruit the histone deacetylase HDAC4 and down-regulate the acetylation level of histone H3 at the carbonic anhydrase IX (CA IX) promoter, thereby down-regulating the expression of CA IX.

In addition, MORC2 is also able to recruit enmethylcer of zeste homolog 2 to promote the trimethylation of H3K27, thereby down-regulating the transcription of the Arg-binding protein 2 gene. It was found that both MORC2 and HSF1 (heat shock factor 1) promoted the binding of PRC2 (polycomb repressive complex 2) and EZH2 to the ArgBP2 enhancer and promoter, enhancing the trimethylation of H3K27, resulting in tight chromatin structure and thus inhibition. ArgBP2 transcription. ArgBP2 is lowly expressed in gastric cancer and can inhibit the proliferation, migration and invasion of gastric cancer cells. Therefore, it is speculated that MORC2 may promote the proliferation, migration and invasion of gastric cancer cells by down-regulating ArgBP2, thereby promoting the occurrence and development of gastric cancer. Moreover, the methionine→isoleucine mutation (M276I) at position 276 of the MORC2 residue regulates the splicing of the cell surface adhesion molecule CD44 protein by heterogeneous nuclear ribonucleoprotein M (hnRNPM), which promotes Migration, infiltration and lung metastasis of triple negative breast cancer.

References:

Sánchez-Solana, Beatriz, Li, D. Q. , & Kumar, R. . (2014). Cytosolic functions of morc2 in lipogenesis and adipogenesis. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1843(2), 316-326.
Tuupanen., et al. (2014). Identification of 33 candidate oncogenes by screening for base-specific mutations. British Journal of Cancer, 111(8), 1657-1662.
Liao, X. H. , Zhang, Y. , Dong, W. J. , Shao, Z. M. , & Li, D. Q. . (2017). Chromatin remodeling protein morc2 promotes breast cancer invasion and metastasis through a prd domain-mediated interaction with ctnnd1. Oncotarget, 8(58), 97941-97954.

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