Chemical perturbations reveal that RUVBL2 regulates the circadian phase in mammals
Authors: Haijiao Zhao
Jiawen Wang
Niu Huang
Luhua Lai
Xiaowen Xie
Chao Tang
Nannan Hou
Noheon Park
Eric Erquan Zhang
Dapeng Ju
Zhiqiang Wang
Shuhua Ying
Xiangbing Qi
Tao Cai
Wei Zhang
Joseph S Takahashi
Guanshen Zhou
Wei Li
Long Mei
Zhancong Xu
Jiawei Yan
Meimei Liao
She Chen
Journal: Science translational medicine (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Transcriptional regulation; circadian clockwork; RUVBL2; clock proteins; chromatin
Affiliations: National Institute of Biological Sciences, Beijing 102206, China., College of Biological Sciences, China Agricultural University, Beijing 100193, China., RPXDs (Suzhou) Co. Ltd., Suzhou City, Jiangsu Province 215028, China., School of Life Sciences, Peking University, Beijing 100871, China., Center for Quantitative Biology, Peking University, Beijing 100871, China., College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China., School of Physics and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China., Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA., Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA., Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China., National Institute of Biological Sciences, Beijing 102206, China.  .

Abstract:  Transcriptional regulation lies at the core of the circadian clockwork, but how the clock-related transcription machinery controls the circadian phase is not understood. Here, we show both in human cells and in mice that RuvB-like ATPase 2 (RUVBL2) interacts with other known clock proteins on chromatin to regulate the circadian phase. Pharmacological perturbation of RUVBL2 with the adenosine analog compound cordycepin resulted in a rapid-onset 12-hour clock phase-shift phenotype at human cell, mouse tissue, and whole-animal live imaging levels. Using simple peripheral injection treatment, we found that cordycepin penetrated the blood-brain barrier and caused rapid entrainment of the circadian phase, facilitating reduced duration of recovery in a mouse jet-lag model. We solved a crystal structure for human RUVBL2 in complex with a physiological metabolite of cordycepin, and biochemical assays showed that cordycepin treatment caused disassembly of an interaction between RUVBL2 and the core clock component BMAL1. Moreover, we showed with spike-in ChIP-seq analysis and binding assays that cordycepin treatment caused disassembly of the circadian super-complex, which normally resides at E-box chromatin loci such as PER1, PER2, DBP, and NR1D1 Mathematical modeling supported that the observed type 0 phase shifts resulted from derepression of E-box clock gene transcription. 

Retracted: No

PubPeer comments:
 The Western blots and other figures in this paper have an interesting layout that appears to be shared with many other papers, as discussed in a January 2020 post on Leonid Schneider s blog: https: forbetterscience.com 2020 01 24 the-full-service-paper-mill-and-its-chinese-customers The list of these papers is available here: https: docs.google.com spreadsheets d 1KXqTAyl4j-jVorFPMD2XRpr76LcIKJ0CVyIvRj0exYQ edit?usp=sharing In almost all papers, Western blot panels within the same figure, and across figures and papers, appear to share the same background, while the bands are regularly spaced, all have similar rounded edges without the usual smudges and specks, and with some bands showing a recognizable  jumping sardine shape. Also in almost all papers, bar graphs show a characteristic layout with bars in solid shades of grey, and the left-most bar in black, as well as double-edged error bars. Many papers have  cell viability and  apoptotic cells graphs. To illustrate the recognizable layout of the graphs in this paper, here is Figure 1. ![file] , 
 Recently retracted. [10 September 2020] .  Retraction: Negative feedback of NFu2010u03baB signaling by long noncoding RNA MALAT1 controls lipopolysaccharideu2010induced inflammation injury in human lung fibroblasts WIu201038 , by Wei Zhu and Xuelin Men, J Cell Biochem. 2020; 1945u20101952: The above article, published online on 21 October 2019 in Wiley Online Library , has been retracted by agreement between the authors, the journal s Editor in Chief, Prof. Dr. Christian Behl, and Wiley Periodicals LLC. The authors asked to retract this manuscript, initially, but were not available for further comments during the investigation.  The retraction has been agreed following an investigation based on allegations raised by a third party. Raw data could not be provided and thus the validity of the overall results could not be confirmed. ,