MORC3

Official Full Name

MORC family CW-type zinc finger 3

Organism

Homo sapiens

GeneID

23515

Background

This gene encodes a protein that localizes to the nuclear matrix and forms nuclear bodies via an ATP-dependent mechanism. The protein is predicted to have coiled-coil and zinc finger domains and has RNA binding activity. Alternative splicing produces multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2016]

Synonyms

NXP2; ZCW5; ZCWCC3;

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Detailed Information

MORC3 (KIAA0136/ZCWCC3/NXP2) was originally identified through a sequencing program designed to understand the structural information of unidentified human genes. The functional map of MORC3 reveals that MORC3 is a nuclear matrix protein that contains a putative RNA binding site in its nuclear matrix binding domain, which is critical for transcriptional regulation. MORC3 is ubiquitously expressed and has a high level of expression in immune cells.

MORC3 Related Regulation

In addition, MORC3 expression was up-regulated in normal peripheral leukocytes after chemotherapy, suggesting that in response to chemotherapy-induced cell damage. MORC3 and other differentially expressed genes may collectively regulate cell survival and apoptosis. It has been reported that MORC3 activates p53 and localizes it in the nucleus of promyelocytic leukemia (PML), thus playing an important role in p53-induced cellular senescence. MORC3 binds to PML proteins via the SUMO and SUMO interaction motifs (SIM). The CW-type zinc finger domain of MORC3 contains an important histone recognition motif specifically for H3K4 methylation and is required for proper localization of MORC3 in the nucleus. In addition, it has been reported that mouse MORC3 can localize to a promoter with H3K4me3 modification in the genome, which is consistent with the ability of MORC3 to bind H3K4me3 in vitro. These evidences suggest that MORC3 plays an important role in DNA damage repair and epigenetic regulation.

Figure 1. Multivalent Chromatin Engagement and Inter-domain Crosstalk Regulate MORC3 ATPase. (Andrews., et al. 2016)

Studies using the Down's syndrome mouse model (Ts65Dn and Ms5Yah) have shown that abnormal regulation of the MORC3 gene is associated with perinatal mortality and growth retardation. Another gene expression profiling of the brain in the Down's syndrome mouse model (Ts1Cje) showed that MORC3 is one of the differentially expressed genes in hippocampus. Functional clustering analysis of MORC3 and other differentially expressed genes revealed that the most prominent signaling pathway in the development of brain after Ts1Cje birth is the interferon-associated JAK-STAT signaling pathway. Other studies have shown that MORC3 interacts with the tyrosine kinase membrane receptor ROR1. ROR1 promotes the survival of acute lymphoblastic leukemia cells by activating downstream signaling pathways such as Akt and MAPK in concert with pre-B cell receptors. The above evidence indicates that MORC3 is involved in cell survival and proliferation-related signaling pathways such as JAK-STAT, Akt and MAPK.

MORC3 and Disease

MORC3 has been identified as an antigen for autoantibodies in approximately 25% of juvenile dermatomyositis (JDM) patients, a form of autoimmune barrier associated with skin calcium deposition. In 2018, Aouizerate et al. found significant myocardial ischemia and the presence of MORC3 (NXP2) autoantibodies in a severe JDM subtype. These anti-MORC3 autoantibodies were also detected in a subpopulation of adult dermatomyositis (ADM) patients. ADM-positive anti-MORC3 autoantibodies have been found in patients with a deciduous pemphigus (an autoimmune blistering disease, ABD). This antibody is present in several other autoimmune disorders, such as lupus erythematosus, rheumatoid arthritis, and systemic lupus erythematosus. Anti-MORC3 autoantibodies were detected in ADM patients with increased risk of cancer, suggesting that anti-MORC3 autoantibodies and other antibodies detected in ADM and autoimmune diseases may be associated with malignancies. In addition, calcifications in JDM patients are associated with increased expression of osteogenic markers, including osteocalcin (OCN), bone salivary protein (BSP), and stromal gla protein (MGP). These evidences suggest that MORC3 is involved in the regulation of calcium homeostasis that plays a key role in bone remodeling.

References:

Andrews, F. H. , Tong, Q. , Sullivan, K. D. , Cornett, E. M. , Zhang, Y. , & Ali, M. , et al. (2016). Multivalent chromatin engagement and inter-domain crosstalk regulate morc3 atpase. Cell Reports, 16(12), 3195-3207.
Aouizerate, J. , De Antonio, M. , Bader-Meunier, B. , Barnerias, C. , Bodemer, C. , & Isapof, A. , et al. (2018). Muscle ischaemia associated with nxp2 autoantibodies: a severe subtype of juvenile dermatomyositis. Rheumatology.
Fujimoto, N. , Takayama, S. , Hamaguchi, Y. , Fujimoto, M. , & Tanaka, T. . (2013). Pemphigus foliaceus associated with anti-nxp2 autoantibody-positive dermatomyositis. Acta Dermato-Venereologica, 94(4).

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