RT Journal Article SR Electronic T1 In silico APC/C substrate discovery reveals cell cycle degradation of chromatin regulators including UHRF1 JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.04.09.033621 DO 10.1101/2020.04.09.033621 A1 Jennifer L. Kernan A1 Raquel C. Martinez-Chacin A1 Xianxi Wang A1 Rochelle L. Tiedemann A1 Thomas Bonacci A1 Rajarshi Choudhury A1 Derek L. Bolhuis A1 Jeffrey S. Damrauer A1 Feng Yan A1 Joseph S. Harrison A1 Michael Ben Major A1 Katherine Hoadley A1 Aussie Suzuki A1 Scott B. Rothbart A1 Nicholas G. Brown A1 Michael J. Emanuele YR 2020 UL http://biorxiv.org/content/early/2020/04/10/2020.04.09.033621.abstract 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 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.Competing Interest StatementThe authors have declared no competing interest.