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
  • 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.