In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators

Authors

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 PacificFollow
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

ORCID

Joseph Harrison: 0000-0002-2118-6524

Document Type

Article

Publication Title

PLoS Biology

Department

Chemistry

ISSN

1544-9173

Volume

18

Issue

12

DOI

10.1371/journal.pbio.3000975

Publication Date

12-11-2020

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

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Franks, J. L., Martinez-Chacin, R. C., Wang, X., Tiedemann, R. L., Bonacci, T., Choudhury, R., Bolhuis, D. L., Enrico, T. P., Mouery, R. D., Damrauer, J. S., Yan, F., Harrison, J. S., Major, M. B., Hoadley, K. A., Suzuki, A., Rothbart, S. B., Brown, N. G., & Emanuele, M. J. (2020). In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators. PLoS Biology, 18(12), DOI: 10.1371/journal.pbio.3000975
https://scholarlycommons.pacific.edu/cop-facarticles/835