SUMMARY Chromatin dynamics play a central role in maintaining genome integrity, but how this is achieved remains largely unknown. Here, we report that microrchidia CW-type zinc finger 2 (MORC2), an uncharacterized protein with a derived PHD finger domain and a conserved GHKL-type ATPase module, is a physiological substrate of p21-activated kinase 1 (PAK1), an important integrator of extracellular signals and nuclear processes. Following DNA damage, MORC2 is phosphorylated on serine 739 in a PAK1 dependent manner, and phosphorylated MORC2 regulates its DNA-dependent ATPase activity to facilitate chromatin remodeling. Moreover, MORC2 associates with chromatin and promotes gamma-H2AX induction in a PAK1 phosphorylation-dependent manner. Consequently, cells expressing MORC2-S739A mutation displayed a reduction in DNA repair efficiency and were hypersensitive to DNA-damaging agent. These findings suggest that the PAK1-MORC2 axis is critical for orchestrating the interplay between chromatin dynamics and the maintenance of genomic integrity through sequentially integrating multiple essential enzymatic processes.

Cancer cells frequently exhibit deregulation of coregulatory molecules to drive the process of growth and metastasis. One such group of ubiquitously expressed coregulators is the metastasis-associated protein (MTA) family, a critical component of nucleosome remodeling and histone deacetylase (NuRD) complex. MTA1 occupies a special place in cancer biology due to its dual corepressor or coactivator nature and widespread overexpression in human cancers. Here, we highlight recent advances in our understanding of the vital roles of MTA1 on transformation, epithelial-mesenchymal transition, and on the functions of key cancer-relevant molecules as a nexus of multiple oncogenes and tumor suppressors. In addition to its paramount role in oncogenesis, we also reveal several new physiological functions of MTA1, related to DNA-damage, inflammatory responses and infection, in which MTA1 functions as a permissive “gatekeeper” for cancer-causing parasites. Further, these discoveries unraveled the versatile multidimensional modes of action of MTA1, which are independent of the NuRD complex and/or transcription. Given the emerging roles of MTA1 in DNA repair, inflammation, and parasitism, we discuss the possibility of MTA1 targeted therapy for use in not only combating cancer but also other inflammation and pathogen-driven pathological conditions.

Metastasis-associated protein 1 (MTA1), a component of the nucleosome remodeling and histone deacetylation (NuRD) complex, is widely upregulated in human cancers. However, the mechanism for regulating its protein stability remains unknown. Here we report that MTA1 is an ubiquitinated protein and targeted by the RING-finger E3 ubiquitin-protein ligase constitutive photomorphogenesis protein 1 (COP1) for degradation via the ubiquitin-proteasome pathway. Induced expression of wild-type COP1 but not its RING motif mutants promotes the ubiquitination and degradation of MTA1, indicating that the ligase activity is required for the COP1-mediated proteolysis of MTA1. Conversely, depletion of endogenous COP1 resulted in a marked decrease in MTA1 ubiquitination, accompanied by a pronounced accumulation of MTA1 protein. MTA1, in turn, destabilizes COP1 by promoting its autoubiquitination, thus creating a tight feedback loop that regulates both MTA1 and COP1 protein stability. Accordingly, disruption of the COP1-mediated proteolysis by ionizing radiation leads to MTA1 stabilization, accompanied by an increased coregulatory function of MTA1 on its target. Furthermore, we discovered that MTA1 is required for optimum DNA double-strand break repair after ionizing radiation. These findings provide novel insights into the regulation of MTA1 protein and reveal a novel function of MTA1 in DNA damage response.coregulator ͉ DNA repair ͉ ubiquitination R egulation of fundamental cellular processes demands dynamic coordinated participation of transcription factors and their coregulators at the target gene chromatin (1, 2), and deregulation of such processes plays a critical role in the development of malignant phenotypes. One emerging family of ubiquitously expressed chromatin modifiers is the metastasisassociated protein (MTA) family, which has an integral role in nucleosome remodeling and histone deacetylation (NuRD) complexes that modify DNA accessibility for cofactors (2, 3). MTA1, the founding member of the MTA family, is widely upregulated in human cancers and plays an important role in tumorigenesis and tumor aggressiveness, especially tumor invasion and metastasis (4-6). MTA1 functions not only as a transcriptional repressor of estrogen receptor ␣ (7), but also as a transcriptional activator on certain promoters, such as the breast cancer-amplified sequence 3 (BCAS3) promoter (8). In this context, MTA1 is acetylated at lysine 626 (K626) by histone acetyltransferase p300; such modification allows MTA1 to recruit RNA polymerase II (Pol II) on the BCAS3 enhancer region and confers its coactivator function upon BCAS3 (8). MTA1 is also a mechanistic mediator of c-Myc-regulated transformation as a downstream target of the oncogene c-Myc (9). Although a paramount role of MTA1 in cancer and coregulator biology, the mechanism for regulating its protein stability remains unknown.Constitutive photomorphogenic 1 (COP1; also known as RFWD2, RING finger and WD repeat domain protein 2), an evolutionarily conserved RING-finger ubiquitin-protei...