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Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control

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  • Irene Gallina
  • Camilla Colding
  • Peter Henriksen
  • Petra Beli
  • Kyosuke Nakamura
  • Judith Offman
  • David P Mathiasen
  • Sonia Silva
  • Eva Hoffmann
  • Anja Groth
  • Chunaram Choudhary
  • Michael Lisby
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DNA replication stress is a source of genomic instability. Here we identify changed mutation rate 1 (Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that Cmr1--together with Mrc1/Claspin, Pph3, the chaperonin containing TCP1 (CCT) and 25 other proteins--define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to Cmr1, its human orthologue WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that Cmr1/WDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins.

Original languageEnglish
JournalNature Communications
Volume6
Pages (from-to)6533
ISSN2041-1723
DOIs
Publication statusPublished - 30 Mar 2015

    Research areas

  • Amino Acid Transport Systems/metabolism, Cell Cycle Checkpoints, Cell Cycle Proteins/genetics, Chaperonin Containing TCP-1/metabolism, Chromatin/metabolism, Chromosomal Proteins, Non-Histone/metabolism, DNA Damage/genetics, DNA-Binding Proteins/metabolism, Genomic Instability, HeLa Cells, Heat-Shock Proteins/metabolism, Humans, Mutation, Phosphoprotein Phosphatases/genetics, Proteasome Endopeptidase Complex, Protein Folding, Proteins/metabolism, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins/genetics, Sumoylation, Ubiquitination

ID: 54999986