2. Academic Validation
  3. APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain

APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain

  • Mol Cell. 2022 Jan 6;82(1):90-105.e13. doi: 10.1016/j.molcel.2021.11.031.
Cole J Ferguson 1,  Olivia Urso 2,  Tatyana Bodrug 3,  Brandon M Gassaway 4,  Edmond R Watson 5,  Jesuraj R Prabu 5,  Pablo Lara-Gonzalez 6,  Raquel C Martinez-Chacin 7,  Dennis Y Wu 2,  Karlla W Brigatti 8,  Erik G Puffenberger 8,  Cora M Taylor 9,  Barbara Haas-Givler 9,  Robert N Jinks 10,  Kevin A Strauss 8,  Arshad Desai 6,  Harrison W Gabel 2,  Steven P Gygi 4,  Brenda A Schulman 5,  Nicholas G Brown 7,  Azad Bonni 11
Affiliations

Affiliations

  • 1 Department of Neuroscience, Washington University, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Neuropathology Division, Physician-Scientist Training Program, Washington University, St. Louis, MO 63110, USA.
  • 2 Department of Neuroscience, Washington University, St. Louis, MO 63110, USA.
  • 3 Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4 Department of Cell Biology, Harvard University, Boston, MA 02138, USA.
  • 5 Max Planck Institute for Biochemistry, Munich, Germany.
  • 6 Department of Cellular and Molecular Medicine, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
  • 7 Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
  • 8 Clinic for Special Children, Strasburg, PA 17579, USA.
  • 9 Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, USA.
  • 10 Department of Biology, Franklin and Marshall College, Lancaster, PA 17603, USA.
  • 11 Department of Neuroscience, Washington University, St. Louis, MO 63110, USA. Electronic address: [email protected].
PMID: 34942119 DOI: 10.1016/j.molcel.2021.11.031
Abstract

Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.

Keywords

APC7; Cdh1; Ki-67; anaphase-promoting complex; brain; chromatin; heterochromatin; neurodevelopment; ubiquitin; ubiquitin ligase.

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