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

Irene Gallina, Camilla Colding, Peter Henriksen, Petra Beli, Kyosuke Nakamura, Judith Offman, David P. Mathiasen, Sonia Silva, Eva Hoffmann, Anja Groth, Chunaram Choudhary and Michael Lisby ()
Additional contact information
Irene Gallina: University of Copenhagen, Room 4.1.07, Copenhagen N DK-2200, Denmark
Camilla Colding: University of Copenhagen, Room 4.1.07, Copenhagen N DK-2200, Denmark
Peter Henriksen: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Petra Beli: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Kyosuke Nakamura: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen
Judith Offman: MRC, Centre for Genome Damage and Stability, School of Life Sciences, University of Sussex
David P. Mathiasen: University of Copenhagen, Room 4.1.07, Copenhagen N DK-2200, Denmark
Sonia Silva: University of Copenhagen, Room 4.1.07, Copenhagen N DK-2200, Denmark
Eva Hoffmann: MRC, Centre for Genome Damage and Stability, School of Life Sciences, University of Sussex
Anja Groth: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen
Chunaram Choudhary: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Michael Lisby: University of Copenhagen, Room 4.1.07, Copenhagen N DK-2200, Denmark

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms7533

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