@article{d391e31973b34fb7886b6d38a9c56fdb,
title = "Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm",
abstract = "Period determination in the mammalian circadian clock involves the turnover rate of the repressors CRY and PER. We show that CRY ubiquitination engages two competing E3 ligase complexes that either lengthen or shorten circadian period in mice. Cloning of a short-period circadian mutant, Past-time, revealed a glycine to glutamate missense mutation in Fbxl21, an F-box protein gene that is a paralog of Fbxl3 that targets the CRY proteins for degradation. While loss of function of FBXL3 leads to period lengthening, mutation of Fbxl21 causes period shortening. FBXL21 forms an SCF E3 ligase complex that slowly degrades CRY in the cytoplasm but antagonizes the stronger E3 ligase activity of FBXL3 in the nucleus. FBXL21 plays a dual role: protecting CRY from FBXL3 degradation in the nucleus and promoting CRY degradation within the cytoplasm. Thus, the balance and cellular compartmentalization of competing E3 ligases for CRY determine circadian period of the clock in mammals.",
author = "Yoo, {Seung Hee} and Mohawk, {Jennifer A.} and Siepka, {Sandra M.} and Yongli Shan and Huh, {Seong Kwon} and Hong, {Hee Kyung} and Izabela Kornblum and Vivek Kumar and Nobuya Koike and Ming Xu and Justin Nussbaum and Xinran Liu and Zheng Chen and Chen, {Zhijian J.} and Green, {Carla B.} and Takahashi, {Joseph S.}",
note = "Funding Information: We thank Choogon Lee for generously providing the anti-PER1 antibody, Homin Kim for LRR3 modeling, Junghea Park, Weimin Song, and Yoga Chelliah for excellent technical support, and Yi Liu for editorial comments on the paper. Research was supported by NIH grants (U01 MH61915, P50 MH074924, and R01 MH078024 to J.S.T.; P50 MH074924 and R01 GM090247 to C.B.G.; R01 GM63692 to Z.J.C.; F32 DA024556 to V.K.), the Howard Hughes Medical Institute (J.S.T. and Z.J.C.), the Welch Foundation (I-1389 to Z.J.C.), and the American Heart Association (11SDG7600045 to Z.C.). J.S.T. and Z.J.C. are Investigators, J.A.M. is an Associate, I.K. is a Laboratory Manager, and S.-H.Y., S.M.S., H.-K.H., and V.K. were Associates at the Howard Hughes Medical Institute. ",
year = "2013",
month = feb,
day = "28",
doi = "10.1016/j.cell.2013.01.055",
language = "English (US)",
volume = "152",
pages = "1091--1105",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}