The Emerging Role of MORC Family Proteins in Cancer Development and Bone Homeostasis GUOJU HONG, 1,2,3 HENG QIU, 3 CHAO WANG, 3 GAURAV JADHAV, 3 HAIBIN WANG, 1,2 JENNIFER TICKNER, 3 WEI HE, 1,2 AND JIAKE XU 1,3 * 1 The National Key Discipline and the Orthopedic Laboratory, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China 2 Department of Orthopedics, First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China 3 School of Pathology Laboratory Medicine, The University of Western Australia, Perth, Western Australia, Australia Microrchidia (MORC or MORC family CW-type zinc finger protein), a highly conserved nuclear protein superfamily, is an interesting new player in signaling-dependent chromatin remodeling and epigenetic regulation. MORC family proteins consist of MORC1, MORC2, MORC3, and MORC4 which display common structural determinants such as CW-type zinc finger and coiled-coil domains. They also exhibit unique structural motifs and tissue-specific expression profiles. MORC1 was first discovered as a key regulator for male meiosis and spermatogenesis. Accumulating biochemical and functional analyses unveil MORC proteins as key regulators for cancer development. More recently, using an ENU mutagenesis mouse model, MORC3 was found to play a role in regulating bone and calcium homeostasis. Here we discuss recent research progress on the emerging role of MORC proteins in cancer development and bone metabolism. Unravelling the cellular and molecular mechanisms by which MORC proteins carry out their functions in a tissue specific manner are important subjects for future investigation. J. Cell. Physiol. 9999: 1–7, 2016. ß 2016 Wiley Periodicals, Inc. MORC or MORC family CW-type zinc finger protein is a novel and highly conserved nuclear matrix protein superfamily with structure domains that link the MORC proteins to signaling- dependent chromatin remodeling and epigenetic regulation (Li et al., 2013). Morc1 was first identified as a regulator for spermatogenesis in male mice (Inoue et al., 1999). To date, four members of the MORC family MORC1, MORC2, MORC3, and MORC4 have been identified whose roles are not restricted to testis formation and male germ cell development. Interestingly, emerging evidence reveals an important role of the MORC members in cancer development and bone homeostasis. For example, MORC1 has been associated with human melanoma, lung cancer, myeloma, and breast cancer (Koslowski et al., 2002; Condomines et al., 2007; Shah et al., 2009); while MORC2 with breast cancer, gastric tumor, and colorectal cancer (Shao et al., 2010; Wang et al., 2010; Chen et al., 2011; Tuupanen et al., 2014; Tong et al., 2015; Wang et al., 2015). MORC3 was recently unveiled as a regulator of cortical bone homeostasis and the haematopoietic stem cell niche (Jadhav et al., 2016), while also being associated with increased cancer risk in dermatomyositis patients (Gunawardena et al., 2009). MORC4 is a potential lymphoma biomarker with high expression in a subset of B-cell lymphomas (Liggins et al., 2007). Current hypothesis proposed that the tissue specific functions of MORC family members might be attributed to their unique structure domain and tissue- specific expression pattern. In this review, we present the molecular structures and expression profiling of MORC family proteins, and discuss the intriguing new role of MORCs in cancer and bone biology, and explore their underlying mechanisms. Molecular Structures and Expression Profiling of MORC Family Proteins To understand the molecular structure and function of MORC family proteins, we analyzed the protein structure and gene expression using web-based programs. Sequence analysis of MORC genes and proteins revealed several conserved domains comprised of a GHKL (DNA gyrase B, Hsp90, DNA mismatch repair enzyme MutL)-ATPase domain at the N-terminus, a conserved CW-type zinc finger domain (four cysteines and two tryptophans) with a putative nuclear localization signal and a coiled-coil motif at the carboxy- terminus (Inoue et al., 1999) (Fig. 1A). Also, mouse family members share similar architectures and domains with human (Fig. 1B). 3D modeling of the predicted structures of MORC family members showed a comparable arrangement in their functional regions and the topology of domain architectures (Fig. 2). It is suggested that MORC proteins play an important function in diverse biological processes like DNA damage response and chromatin remodeling. The GHKL-type ATPase motif is involved in DNA metabolism and signaling transduction (Iyer et al., 2008). MORC2B carries a much longer Guoju Hong and Heng Qiu contributed equally to the work. Contract grant sponsor: National Health and Medical Research Council; Contract grant number: NHMRC No: APP1107828. *Correspondence to: Jiake Xu, School of Pathology and Laboratory Medicine, The University of Western Australia, QEII Medical Centre, 1st Floor M Block, Nedlands WA 6009, Australia. E-mail: Jiake.xu@uwa.edu.au Manuscript Received: 26 October 2016 Manuscript Accepted: 26 October 2016 Accepted manuscript online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2015. DOI: 10.1002/jcp.25665 MINI-REVIEW 1 Journal of Journal of Cellular Physiology Cellular Physiology © 2016 WILEY PERIODICALS, INC.