The P-loop NTPase RUVBL2 is a conserved clock component across eukaryotes

Meimei Liao, Yanqin Liu, Zhancong Xu, Mingxu Fang, Ziqing Yu, Yufan Cui, Zhengda Sun, Ran Huo, Jieyu Yang, Fusheng Huang, Mingming Liu, Qin Zhou, Xiaocui Song, Hui Han, She Chen, Xiaodong Xu, Ximing Qin, Qun He, Dapeng Ju, Tao Wang, Nirav Thakkar, Paul E. Hardin, Susan S. Golden and Eric Erquan Zhang ()
Additional contact information
Meimei Liao: National Institute of Biological Sciences
Yanqin Liu: National Institute of Biological Sciences
Zhancong Xu: National Institute of Biological Sciences
Mingxu Fang: University of California, San Diego
Ziqing Yu: National Institute of Biological Sciences
Yufan Cui: National Institute of Biological Sciences
Zhengda Sun: National Institute of Biological Sciences
Ran Huo: National Institute of Biological Sciences
Jieyu Yang: National Institute of Biological Sciences
Fusheng Huang: China Agricultural University
Mingming Liu: Henan University
Qin Zhou: Anhui University
Xiaocui Song: National Institute of Biological Sciences
Hui Han: National Institute of Biological Sciences
She Chen: National Institute of Biological Sciences
Xiaodong Xu: Henan University
Ximing Qin: Anhui University
Qun He: China Agricultural University
Dapeng Ju: Chongqing Medical University
Tao Wang: National Institute of Biological Sciences
Nirav Thakkar: Texas A&M University
Paul E. Hardin: Texas A&M University
Susan S. Golden: University of California, San Diego
Eric Erquan Zhang: National Institute of Biological Sciences

Nature, 2025, vol. 642, issue 8066, 165-173

Abstract: Abstract The eukaryotic circadian clock keeps time by using a transcription–translation feedback loop, which exhibits an architecture that is conserved across a diverse range of organisms, including fungi, plants and animals1. Despite their mechanistic similarity, the molecular components of these clocks indicate a lack of common ancestry2. Our study reveals that RUVBL2, which is a P-loop NTPase enzyme previously shown to affect circadian phase and amplitude as part of mammalian clock super-complexes, influences the circadian period through its remarkably slow ATPase activity, resembling the well-characterized KaiC-based clock in cyanobacteria. A screen of RUVBL2 variants identified arrhythmic, short-period and long-period mutants that altered circadian locomotor activity rhythms following delivery by adeno-associated virus to the murine suprachiasmatic nucleus. Enzymatic assays showed that wild-type RUVBL2 hydrolyses only around 13 ATP molecules a day, a vastly reduced turnover compared with typical ATPases. Notably, physical interactions between RUVBL2 orthologues and core clock proteins in humans, Drosophila and the fungus Neurospora, along with consistent circadian phenotypes of RUVBL2-mutant orthologues across species, reinforce their clock-related function in eukaryotes. Thus, as well as establishing RUVBL2 as a common core component in eukaryotic clocks, our study supports the idea that slow ATPase activity, initially discovered in cyanobacteria, is a shared feature of eukaryotic clocks.

Date: 2025
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DOI: 10.1038/s41586-025-08797-3

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