TY - JOUR
T1 - In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators
AU - Franks, Jennifer L.
AU - Martinez-Chacin, Raquel C.
AU - Wang, Xianxi
AU - Tiedemann, Rochelle L.
AU - Bonacci, Thomas
AU - Choudhury, Rajarshi
AU - Bolhuis, Derek L.
AU - Enrico, Taylor P.
AU - Mouery, Ryan D.
AU - Damrauer, Jeffrey S.
AU - Yan, Feng
AU - Harrison, Joseph S.
AU - Major, M. Ben
AU - Hoadley, Katherine A.
AU - Suzuki, Aussie
AU - Rothbart, Scott B.
AU - Brown, Nicholas G.
AU - Emanuele, Michael J.
N1 - Publisher Copyright:
© 2020 Franks et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/12/11
Y1 - 2020/12/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85097678650&partnerID=8YFLogxK
U2 - 10.1371/journal.pbio.3000975
DO - 10.1371/journal.pbio.3000975
M3 - Article
C2 - 33306668
AN - SCOPUS:85097678650
SN - 1544-9173
VL - 18
JO - PLoS Biology
JF - PLoS Biology
IS - 12
M1 - e3000975
ER -