2. Academic Validation
  3. The P-loop NTPase RUVBL2 is a conserved clock component across eukaryotes

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

  • Nature. 2025 Mar 26. doi: 10.1038/s41586-025-08797-3.
Meimei Liao # 1,  Yanqin Liu # 1 2,  Zhancong Xu # 1 3,  Mingxu Fang 4,  Ziqing Yu 1 3,  Yufan Cui 1 5,  Zhengda Sun 1 3,  Ran Huo 1 5,  Jieyu Yang 1,  Fusheng Huang 6,  Mingming Liu 7,  Qin Zhou 8,  Xiaocui Song 1,  Hui Han 1,  She Chen 1,  Xiaodong Xu 7,  Ximing Qin 8,  Qun He 6,  Dapeng Ju 9,  Tao Wang 1 5,  Nirav Thakkar 10,  Paul E Hardin 10,  Susan S Golden 4 11,  Eric Erquan Zhang 12 13
Affiliations

Affiliations

  • 1 National Institute of Biological Sciences, Beijing, China.
  • 2 Peking University-Tsinghua University-National Institute of Biological Sciences (PTN) Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing, China.
  • 3 Graduate Program, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
  • 4 Center for Circadian Biology, University of California, San Diego, La Jolla, CA, USA.
  • 5 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
  • 6 College of Biological Sciences, China Agricultural University, Beijing, China.
  • 7 State Key Laboratory of Crop Stress Adaptation and Improvement, School of Life Sciences, Henan University, Kaifeng, China.
  • 8 Institute of Health Sciences and Technology, Institutes of Physical Science and Information Technology, Anhui University, Hefei, China.
  • 9 Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 10 Department of Biology and Center for Biological Clocks Research, Texas A&M University, College Station, TX, USA.
  • 11 Department of Molecular Biology, University of California, San Diego, La Jolla, CA, USA.
  • 12 National Institute of Biological Sciences, Beijing, China. zhangerquan@nibs.ac.cn.
  • 13 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. zhangerquan@nibs.ac.cn.
  • # Contributed equally.
PMID: 40140583 DOI: 10.1038/s41586-025-08797-3
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.

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