In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators.
Anaphase-Promoting Complex-Cyclosome
/ metabolism
CCAAT-Enhancer-Binding Proteins
/ genetics
Cell Cycle
/ physiology
Cell Cycle Proteins
/ metabolism
Cell Line
Chromatin
/ genetics
Computer Simulation
HEK293 Cells
HeLa Cells
Humans
Protein Processing, Post-Translational
Transcription Factors
/ metabolism
Ubiquitin-Protein Ligases
/ metabolism
Ubiquitination
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
10
01
2020
accepted:
05
11
2020
revised:
23
12
2020
pubmed:
12
12
2020
medline:
3
2
2021
entrez:
11
12
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33306668
doi: 10.1371/journal.pbio.3000975
pii: PBIOLOGY-D-20-00069
pmc: PMC7758050
doi:
Substances chimiques
CCAAT-Enhancer-Binding Proteins
0
Cell Cycle Proteins
0
Chromatin
0
Transcription Factors
0
Anaphase-Promoting Complex-Cyclosome
EC 2.3.2.27
UHRF1 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3000975Subventions
Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007040
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM120309
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA071341
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM128855
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124736
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM134231
Pays : United States
Déclaration de conflit d'intérêts
I have read the journal's policy and the authors of this manuscript have the following competing interests: NGB is a consultant for Cullgen, Inc.
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