2. Academic Validation
  3. RAD23B acquires a copper metalloadaptor function in amphibian-to-reptile evolution to increase metabolism and regulate genomic integrity

RAD23B acquires a copper metalloadaptor function in amphibian-to-reptile evolution to increase metabolism and regulate genomic integrity

  • Mol Cell. 2025 Sep 18;85(18):3443-3459.e11. doi: 10.1016/j.molcel.2025.08.024.
Tong Xiao 1,  Dan He 2,  Danqian Liu 3,  Shang Jia 4,  Qingyi Chen 4,  Daniel Silverman 3,  Neilabjo Maitra 4,  Alan Y Huang 4,  Aidan Pezacki 1,  Trisha T Nguyen 5,  Guodong Rao 5,  Rachel Tillage 6,  Kelly Deng 1,  David Weinshenker 6,  R David Britt 5,  Mark J S Kelly 7,  Yang Dan 8,  Christopher J Chang 9
Affiliations

Affiliations

  • 1 Department of Chemistry, Princeton University, Princeton, NJ, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
  • 2 Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
  • 3 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • 4 Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
  • 5 Department of Chemistry, University of California, Davis, Davis, CA, USA.
  • 6 Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA.
  • 7 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
  • 8 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
  • 9 Department of Chemistry, Princeton University, Princeton, NJ, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA. Electronic address: chrischang@princeton.edu.
PMID: 40972527 DOI: 10.1016/j.molcel.2025.08.024
Abstract

Increasing brain complexity is a major step in the evolution of species. Here, we show that, in the transition from amphibians to reptiles, the DNA repair protein RAD23B acquires a metalloadaptor function that allows it to serve as a central hub for both metabolism and protection of genomic integrity. More specifically, RAD23B gains an allosteric H274/H323 copper-binding site to enable the transfer of copper from the universal copper transporter 1 (CTR1) uptake protein to all known copper metallochaperone pathways, while simultaneously making its canonical functions in DNA repair copper dependent. This layer of nutrient regulation allows organisms to withstand elevated levels of potentially toxic copper while augmenting metabolism in cells with high energetic needs across both physiology and disease, including neurons in the locus coeruleus, a key brain structure that regulates sleep, and Cancer cells.

Keywords

Amniota evolution; CTR1/SLC31A1; Rad23b; metalloadaptor; metalloallostery; mitochondrial metabolism; sleep and wake behavior; transition metal signaling.

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