SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway

Ching Shyi Wu, Jian Ouyang, Eiichiro Mori, Hai Dang Nguyen, Alexandre Maréchal, Alexander Hallet, David J. Chen, Lee Zou

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1472-1484
Number of pages13
JournalGenes and Development
Volume28
Issue number13
DOIs
StatePublished - Jul 1 2014

Keywords

  • ATR
  • ATRIP
  • Checkpoint
  • SUMOylation

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Wu, C. S., Ouyang, J., Mori, E., Nguyen, H. D., Maréchal, A., Hallet, A., Chen, D. J., & Zou, L. (2014). SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway. Genes and Development, 28(13), 1472-1484. https://doi.org/10.1101/gad.238535.114