2. Academic Validation
  3. The anaphase-promoting complex controls a ubiquitination-phosphoprotein axis in chromatin during neurodevelopment

The anaphase-promoting complex controls a ubiquitination-phosphoprotein axis in chromatin during neurodevelopment

  • Dev Cell. 2023 Oct 18:S1534-5807(23)00521-X. doi: 10.1016/j.devcel.2023.10.002.
Leya Ledvin 1,  Brandon M Gassaway 2,  Jonathan Tawil 1,  Olivia Urso 1,  Donald Pizzo 1,  Kaeli A Welsh 3,  Derek L Bolhuis 4,  Daniel Fisher 5,  Azad Bonni 6,  Steven P Gygi 2,  Nicholas G Brown 3,  Cole J Ferguson 7
Affiliations

Affiliations

  • 1 Pathology Department, University of California, San Diego, La Jolla, CA 92093, USA.
  • 2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
  • 4 Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
  • 5 Institute of Genetics, Montpelier, France.
  • 6 Neuroscience Department, Washington University, St. Louis, MO 63110, USA.
  • 7 Pathology Department, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].
PMID: 37875116 DOI: 10.1016/j.devcel.2023.10.002
Abstract

Mutations in the degradative ubiquitin ligase anaphase-promoting complex (APC) alter neurodevelopment by impairing proteasomal protein clearance, but our understanding of their molecular and cellular pathogenesis remains limited. Here, we employ the proteomic-based discovery of APC substrates in APC mutant mouse brain and human cell lines and identify the chromosome-passenger complex (CPC), Topoisomerase 2a (Top2a), and Ki-67 as major chromatin factors targeted by the APC during neuronal differentiation. These substrates accumulate in phosphorylated form, suggesting that they fail to be eliminated after mitosis during terminal differentiation. The accumulation of the CPC kinase Aurora B within constitutive heterochromatin and hyperphosphorylation of its target histone 3 are corrected in the mutant brain by pharmacologic Aurora B inhibition. Surprisingly, the reduction of Ki-67, but not H3S10ph, rescued the function of constitutive heterochromatin in APC mutant neurons. These results expand our understanding of how ubiquitin signaling regulates chromatin during neurodevelopment and identify potential therapeutic targets in APC-related disorders.

Keywords

H3S10ph; Ki-67; anaphase-promoting complex; chromatin; chromosome-passenger complex; heterochromatin; neurodevelopment; proteomics/phosphoproteomics; topoisomerase; ubiquitin ligase.

Figures
Products