In silico APC/C substrate discovery reveals cell cycle degradation of chromatin regulators including UHRF1

BioRxiv : the Preprint Server for Biology
J. KernanMichael J Emanuele


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 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.

Related Concepts

CFC1 gene
Saccharomyces cerevisiae allergenic extract
Regulation of Biological Process
Gene-Environment Interaction
Genetic Activator
Grapevine cryptic virus

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.

Related Papers

Methods in Molecular Biology
Marc A JarvisJan-Michael Peters
Annual Review of Cell and Developmental Biology
Jillian A Pesin, Terry L Orr-Weaver
© 2020 Meta ULC. All rights reserved