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

Irene Gallina; Camilla Skettrup Colding; Peter Henriksen; Petra Beli; Kyosuke Nakamura; Judith Offman; David Plesner Barfred; Sonia Cristina Pinela da Silva; Eva Hoffmann; Anja Groth; Chunaram Choudhary; Michael Lisby

doi:10.1038/ncomms7533

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

Irene Gallina, Camilla Skettrup Colding, Peter Henriksen, Petra Beli, Kyosuke Nakamura, Judith Offman, David Plesner Barfred, Sonia Cristina Pinela da Silva, Eva Hoffmann, Anja Groth, Chunaram Choudhary, Michael Lisby

Functional Genomics

47 Citations (Scopus)

208 Downloads (Pure)

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.

Original language	English
Article number	6533
Journal	Nature Communications
Volume	6
Number of pages	16
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms7533
Publication status	Published - Mar 2015

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Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality controlFinal published version, 3.13 MBLicence: CC BY

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

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.",

author = "Irene Gallina and Colding, {Camilla Skettrup} and Peter Henriksen and Petra Beli and Kyosuke Nakamura and Judith Offman and Barfred, {David Plesner} and {Pinela da Silva}, {Sonia Cristina} and Eva Hoffmann and Anja Groth and Chunaram Choudhary and Michael Lisby",

year = "2015",

month = mar,

doi = "10.1038/ncomms7533",

language = "English",

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journal = "Nature Communications",

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T1 - Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control

AU - Gallina, Irene

AU - Colding, Camilla Skettrup

AU - Henriksen, Peter

AU - Beli, Petra

AU - Nakamura, Kyosuke

AU - Offman, Judith

AU - Barfred, David Plesner

AU - Pinela da Silva, Sonia Cristina

AU - Hoffmann, Eva

AU - Groth, Anja

AU - Choudhary, Chunaram

AU - Lisby, Michael

PY - 2015/3

Y1 - 2015/3

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms7533

DO - 10.1038/ncomms7533

M3 - Journal article

C2 - 25817432

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6533

ER -

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

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