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

Cole J. Ferguson, Olivia Urso, Tatyana Bodrug, Brandon M. Gassaway, Edmond R. Watson, Jesuraj R. Prabu, Pablo Lara-Gonzalez, Raquel C. Martinez-Chacin, Dennis Y. Wu, Karlla W. Brigatti, Erik G. Puffenberger, Cora M. Taylor, Barbara Haas-Givler, Robert N. Jinks, Kevin A. Strauss, Arshad Desai, Harrison W. Gabel, Steven P. Gygi, Brenda A. Schulman, Nicholas G. BrownAzad Bonni

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)90-105.e13
JournalMolecular cell
Volume82
Issue number1
DOIs
StatePublished - Jan 6 2022

Keywords

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

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