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The E3 ubiquitin ligase UBE3A is an integral component of the molecular circadian clock through regulating the BMAL1 transcription factor
Open accessAbstract
Post-translational modifications (such as ubiquitination) of clock proteins are critical in maintaining the precision and robustness of the evolutionarily conserved circadian clock. Ubiquitination of the core clock transcription factor BMAL1 (brain and muscle Arnt-like 1) has recently been reported. However, it remains unknown whether BMAL1 ubiquitination affects circadian pacemaking and what ubiquitin ligase(s) is involved. Here, we show that activating UBE3A (by expressing viral oncogenes E6/E7) disrupts circadian oscillations in mouse embryonic fibroblasts, measured using PER2::Luc dynamics, and rhythms in endogenous messenger ribonucleic acid and protein levels of BMAL1. Over-expression of E6/E7 reduced the level of BMAL1, increasing its ubiquitination and proteasomal degradation. UBE3A could bind to and degrade BMAL1 in a ubiquitin ligase-dependent manner. This occurred both in the presence and absence of E6/E7. We provide in vitro (knockdown/over-expression in mammalian cells) and in vivo (genetic manipulation in Drosophila) evidence for an endogenous role of UBE3A in regulating circadian dynamics and rhythmic locomotor behaviour. Together, our data reveal an essential and conserved role of UBE3A in the regulation of the circadian system in mammals and flies and identify a novel mechanistic link between oncogene E6/E7-mediated cell transformation and circadian (BMAL1) disruption.
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“UBE3A targets the circadian transcription factor BMAL1 for proteasomal degradation and thus is crucial for maintaining the pace of molecular clock timing117.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [117]
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Metadata
- Authors
- Gossan, N. C., Zhang, F., Guo, B., Jin, D., Yoshitane, H., Yao, A., Glossop, N., Zhang, Y. Q., Fukada, Y., & Meng, Q.-J.
- Affiliations
- University of Manchester (GB)
- The University of Tokyo (JP)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Meng, Qing-Jun
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-04-11
- Volume
- 42
- Issue
- 9
- Pages
- 5765-5775
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC4027211
- OpenAlex
- W2156456978
- Cited by
- 106
- References
- 39
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 4 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 11 · 2019: 12 · 2018: 15 · 2017: 9 · 2016: 6 · 2015: 12 · 2014: 3
- FWCI
- 4.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nucleic Acids Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Funders
- Wellcome Trust
- University of Manchester
- National Natural Science Foundation of China
- Medical Research Council (G0900414)
- Biotechnology and Biological Sciences Research Council (BB/H531600/1)
- Japan Society for the Promotion of Science (24227001)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Light effects on plants
- Keywords
- UBE3A, Bmal1, circadian clock, ubiquitination, E6 and E7 oncogenes, proteasomal degradation, clock proteins, locomotor rhythm, cell transformation, mouse embryonic fibroblasts
- MeSH terms
- Animals, Drosophila melanogaster, Gene Expression Regulation, Gene Expression, Drosophila Proteins, NIH 3T3 Cells, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Mice, Ubiquitination, ARNTL Transcription Factors, Circadian Clocks, Proteolysis
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