4.6 Article

ATR activation is regulated by dimerization of ATR activating proteins

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JOURNAL OF BIOLOGICAL CHEMISTRY
卷 296, 期 -, 页码 -

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ELSEVIER
DOI: 10.1016/j.jbc.2021.100455

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  1. National Institutes of Health [R01CA239161]
  2. National Institutes of Health, United States [P50CA098131]

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TOPBP1 and ETAA1 are two activators of ATR, which activate ATR through the same biochemical mechanism. Dimerization of both TOPBP1 and ETAA1 is crucial for optimal ATR signaling and genome stability.
The checkpoint kinase ATR regulates DNA repair, cell cycle progression, and other DNA damage and replication stress responses. ATR signaling is stimulated by an ATR activating protein, and in metazoan cells, there are at least two ATR activators: TOPBP1 and ETAA1. Current evidence indicates TOPBP1 and ETAA1 activate ATR via the same biochemical mechanism, but several aspects of this mechanism remain undefined. For example, ATR and its obligate binding partner ATR interacting protein (ATRIP) form a tetrameric complex consisting of two ATR and two ATRIP molecules, but whether TOPBP1 or ETAA1 dimerization is similarly required for ATR function is unclear. Here, we show that fusion of the TOPBP1 and ETAA1 ATR activation domains (AADs) to dimeric tags makes them more potent activators of ATR in vitro. Furthermore, induced dimerization of both AADs using chemical dimerization of a modified FKBP tag enhances ATR kinase activation and signaling in cells. ETAA1 forms oligomeric complexes mediated by regions of the protein that are predicted to be intrinsically disordered. Induced dimerization of a mini-ETAA1 protein that contains the AAD and Replication Protein A (RPA) interaction motifs enhances ATR signaling, rescues cellular hypersensitivity to DNA damaging agents, and suppresses micronuclei formation in ETAA1-deficient cells. Together, our results indicate that TOPBP1 and ETAA1 dimerization is important for optimal ATR signaling and genome stability.

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