title: Multivalent Chromatin Engagement and Inter-domain Crosstalk Regulate MORC3 ATPase.
abstract: MORC3 is linked to inflammatory myopathies and cancer; however, the precise role of MORC3 in normal cell physiology and disease remains poorly understood. Here, we present detailed genetic, biochemical, and structural analyses of MORC3. We demonstrate that MORC3 is significantly upregulated in Down syndrome and that genetic abnormalities in MORC3 are associated with cancer. The CW domain of MORC3 binds to the methylated histone H3K4 tail, and this interaction is essential for recruitment of MORC3 to chromatin and accumulation in nuclear bodies. We show that MORC3 possesses intrinsic ATPase activity that requires DNA, but it is negatively regulated by the CW domain, which interacts with the ATPase domain. Natively linked CW impedes binding of the ATPase domain to DNA, resulting in a decrease in the DNA-stimulated enzymatic activity. Collectively, our studies provide a molecular framework detailing MORC3 functions and suggest that its modulation may contribute to human disease.
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Forest H
authors.initials: FH
authors.lastname: Andrews
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Sullivan
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Evan M
authors.initials: EM
authors.lastname: Cornett
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Ali
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: JaeWoo
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Ahway
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Department of Biochemistry and Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Angela H
authors.initials: AH
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Strahl
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Costello
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Joaquin M
authors.initials: JM
authors.lastname: Espinosa
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Rothbart
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: tatiana.kutateladze@ucdenver.edu.
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Kutateladze
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism; D000071677:Histidine Kinase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D000072417:Protein Domains
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D000071677:Histidine Kinase; D000251:Adenosine Triphosphatases; C551732:MORC3 protein, human