Delineation of a minimal topoisomerase II binding protein 1 for regulated activation of ATR at DNA double-strand breaks.

Autor:	Ruis K; Department of Biological Sciences, Molecular and Computational Biology Section, University of Southern California, Los Angeles, California, USA., Huynh O; Department of Biological Sciences, Molecular and Computational Biology Section, University of Southern California, Los Angeles, California, USA., Montales K; Department of Biological Sciences, Molecular and Computational Biology Section, University of Southern California, Los Angeles, California, USA., Barr NA; Department of Biological Sciences, Molecular and Computational Biology Section, University of Southern California, Los Angeles, California, USA., Michael WM; Department of Biological Sciences, Molecular and Computational Biology Section, University of Southern California, Los Angeles, California, USA. Electronic address: mattm@usc.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2022 Jul; Vol. 298 (7), pp. 101992. Date of Electronic Publication: 2022 Apr 28.
DOI:	10.1016/j.jbc.2022.101992
Abstrakt:	Topoisomerase II Binding Protein 1 (TOPBP1) is an important activator of the DNA damage response kinase Ataxia Telangiectasia and Rad3-related (ATR), although the mechanism by which this activation occurs is not yet known. TOPBP1 contains nine copies of the BRCA1 C-terminal repeat (BRCT) motif, which allows protein-protein and protein-DNA interactions. TOPBP1 also contains an ATR activation domain (AAD), which physically interacts with ATR and its partner ATR-interacting protein (ATRIP) in a manner that stimulates ATR kinase activity. It is unclear which of TOPBP1's nine BRCT domains participate in the reaction, as well as the individual roles played by these relevant BRCT domains. To address this knowledge gap, here, we delineated a minimal TOPBP1 that can activate ATR at DNA double-strand breaks in a regulated manner. We named this minimal TOPBP1 "Junior" and we show that Junior is composed of just three regions: BRCT0-2, the AAD, and BRCT7&8. We further defined the individual functions of these three regions by showing that BRCT0-2 is required for recruitment to DNA double-strand breaks and is dispensable thereafter, and that BRCT7&8 is dispensable for recruitment but essential to allow the AAD to multimerize and activate ATR. The delineation of TOPBP1 Junior creates a leaner, simplified, and better understood TOPBP1 and provides insight into the mechanism of ATR activation. Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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