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SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway
The ATR (ATM [ataxia telangiectasia-mutated]- and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR–Chk1 kinase cascade, whether post-translational modifications other than phosphorylation are important f...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083090/ https://www.ncbi.nlm.nih.gov/pubmed/24990965 http://dx.doi.org/10.1101/gad.238535.114 |
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author | Wu, Ching-Shyi Ouyang, Jian Mori, Eiichiro Nguyen, Hai Dang Maréchal, Alexandre Hallet, Alexander Chen, David J. Zou, Lee |
author_facet | Wu, Ching-Shyi Ouyang, Jian Mori, Eiichiro Nguyen, Hai Dang Maréchal, Alexandre Hallet, Alexander Chen, David J. Zou, Lee |
author_sort | Wu, Ching-Shyi |
collection | PubMed |
description | The ATR (ATM [ataxia telangiectasia-mutated]- and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR–Chk1 kinase cascade, whether post-translational modifications other than phosphorylation are important for this pathway remains largely unknown. Here, we show that protein SUMOylation plays a key role in the ATR pathway. ATRIP, the regulatory partner of ATR, is modified by SUMO2/3 at K234 and K289. An ATRIP mutant lacking the SUMOylation sites fails to localize to DNA damage and support ATR activation efficiently. Surprisingly, the ATRIP SUMOylation mutant is compromised in the interaction with a protein group, rather than a single protein, in the ATR pathway. Multiple ATRIP-interacting proteins, including ATR, RPA70, TopBP1, and the MRE11–RAD50–NBS1 complex, exhibit reduced binding to the ATRIP SUMOylation mutant in cells and display affinity for SUMO2 chains in vitro, suggesting that they bind not only ATRIP but also SUMO. Fusion of a SUMO2 chain to the ATRIP SUMOylation mutant enhances its interaction with the protein group and partially suppresses its localization and functional defects, revealing that ATRIP SUMOylation promotes ATR activation by providing a unique type of protein glue that boosts multiple protein interactions along the ATR pathway. |
format | Online Article Text |
id | pubmed-4083090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-40830902015-01-01 SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway Wu, Ching-Shyi Ouyang, Jian Mori, Eiichiro Nguyen, Hai Dang Maréchal, Alexandre Hallet, Alexander Chen, David J. Zou, Lee Genes Dev Research Paper The ATR (ATM [ataxia telangiectasia-mutated]- and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR–Chk1 kinase cascade, whether post-translational modifications other than phosphorylation are important for this pathway remains largely unknown. Here, we show that protein SUMOylation plays a key role in the ATR pathway. ATRIP, the regulatory partner of ATR, is modified by SUMO2/3 at K234 and K289. An ATRIP mutant lacking the SUMOylation sites fails to localize to DNA damage and support ATR activation efficiently. Surprisingly, the ATRIP SUMOylation mutant is compromised in the interaction with a protein group, rather than a single protein, in the ATR pathway. Multiple ATRIP-interacting proteins, including ATR, RPA70, TopBP1, and the MRE11–RAD50–NBS1 complex, exhibit reduced binding to the ATRIP SUMOylation mutant in cells and display affinity for SUMO2 chains in vitro, suggesting that they bind not only ATRIP but also SUMO. Fusion of a SUMO2 chain to the ATRIP SUMOylation mutant enhances its interaction with the protein group and partially suppresses its localization and functional defects, revealing that ATRIP SUMOylation promotes ATR activation by providing a unique type of protein glue that boosts multiple protein interactions along the ATR pathway. Cold Spring Harbor Laboratory Press 2014-07-01 /pmc/articles/PMC4083090/ /pubmed/24990965 http://dx.doi.org/10.1101/gad.238535.114 Text en © 2014 Wu et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Paper Wu, Ching-Shyi Ouyang, Jian Mori, Eiichiro Nguyen, Hai Dang Maréchal, Alexandre Hallet, Alexander Chen, David J. Zou, Lee SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway |
title | SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway |
title_full | SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway |
title_fullStr | SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway |
title_full_unstemmed | SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway |
title_short | SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway |
title_sort | sumoylation of atrip potentiates dna damage signaling by boosting multiple protein interactions in the atr pathway |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083090/ https://www.ncbi.nlm.nih.gov/pubmed/24990965 http://dx.doi.org/10.1101/gad.238535.114 |
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