RT Journal Article
SR Electronic
T1 Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein MDM2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 286708
DO 10.1101/286708
A1 JingJing Liu
A1 Xianlin Zou
A1 Tetsuya Gotoh
A1 Anne M. Brown
A1 Liang Jiang
A1 Jae Kyoung Kim
A1 Carla V. Finkielstein
YR 2018
UL http://biorxiv.org/content/early/2018/03/21/286708.abstract
AB The circadian clock relies on post-translational modifications to set the timing for degradation of core regulatory components and, thus, sets clock progression. Ubiquitin-modifying enzymes targeting clock components for degradation are known to mostly recognize phosphorylated substrates. A case in point is the circadian factor PERIOD 2 (PER2) whose phospho-specific turnover involves its recognition by β-transducin repeat containing proteins (β-TrCPs). Yet, the existence of this unique mode of regulation of PER2’s stability falls short of explaining persistent oscillatory phenotypes reported in biological systems lacking functional elements of the phospho-dependent PER2 degradation machinery.In this study, we challenge the phosphorylation-centric view that PER2 degradation enhances circadian rhythm robustness by i) identifying the PER2:MDM2 endogenous complex, ii) establishing PER2 as a previously uncharacterized substrate for MDM2, iii) revealing an alternative phosphorylation-independent mechanism for PER2 ubiquitin-mediated degradation, iv) pinpointing residues for ubiquitin modification, and v) establishing the importance of MDM2-mediated PER2 turnover for defining the circadian period length. Our results not only expand MDM2’s suite of specific substrates beyond the cell cycle to include circadian components but also uncover novel regulatory players that likely impact our view of how other mechanisms crosstalk and modulate the clock itself.