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Selected Works of Joseph Harrison
Article
In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators
PLoS Biology
  • Jennifer L. Franks, The University of North Carolina at Chapel Hill
  • Raquel C. Martinez-Chacin, The University of North Carolina at Chapel Hill
  • Xianxi Wang, The University of North Carolina at Chapel Hill
  • Rochelle L. Tiedemann, Van Andel Research Institute
  • Thomas Bonacci, The University of North Carolina at Chapel Hill
  • Rajarshi Choudhury, The University of North Carolina at Chapel Hill
  • Derek L. Bolhuis, The University of North Carolina at Chapel Hill
  • Taylor P. Enrico, The University of North Carolina at Chapel Hill
  • Ryan D. Mouery, The University of North Carolina at Chapel Hill
  • Jeffrey S. Damrauer, The University of North Carolina at Chapel Hill
  • Feng Yan, The University of North Carolina at Chapel Hill
  • Joseph S. Harrison, University of the Pacific
  • M. Ben Major, Washington University in St. Louis
  • Katherine A. Hoadley, The University of North Carolina at Chapel Hill
  • Aussie Suzuki, McArdle Laboratory for Cancer Research
  • Scott B. Rothbart, Van Andel Research Institute
  • Nicholas G. Brown, The University of North Carolina at Chapel Hill
  • Michael J. Emanuele, The University of North Carolina at Chapel Hill
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ORCID
Joseph Harrison: 0000-0002-2118-6524
Document Type
Article
Department
Chemistry
DOI
10.1371/journal.pbio.3000975
Publication Date
12-11-2020
Disciplines
Abstract

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and critical regulator of cell cycle progression. Despite its vital role, it has remained challenging to globally map APC/C substrates. By combining orthogonal features of known substrates, we predicted APC/C substrates in silico. This analysis identified many known substrates and suggested numerous candidates. Unexpectedly, chromatin regulatory proteins are enriched among putative substrates, and we show experimentally that several chromatin proteins bind APC/C, oscillate during the cell cycle, and are degraded following APC/C activation, consistent with being direct APC/C substrates. Additional analysis revealed detailed mechanisms of ubiquitylation for UHRF1, a key chromatin regulator involved in histone ubiquitylation and DNA methylation maintenance. Disrupting UHRF1 degradation at mitotic exit accelerates G1-phase cell cycle progression and perturbs global DNA methylation patterning in the genome. We conclude that APC/C coordinates crosstalk between cell cycle and chromatin regulatory proteins. This has potential consequences in normal cell physiology, where the chromatin environment changes depending on proliferative state, as well as in disease. Copyright:

Comments
Funding Sponsor: National Institute of General Medical Sciences, R01GM120309
Creative Commons License
Creative Commons Attribution 4.0 International
Citation Information
Jennifer L. Franks, Raquel C. Martinez-Chacin, Xianxi Wang, Rochelle L. Tiedemann, et al.. "In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators" PLoS Biology Vol. 18 Iss. 12 (2020) ISSN: 1544-9173
Available at: http://works.bepress.com/joseph-harrison/41/