The protein phosphatase EYA4 promotes homologous recombination (HR) through dephosphorylation of tyrosine 315 on RAD51
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Date
2024
Authors
Avalos, B.D.L.P.
Paquet, N.
Tropée, R.
Coulombe, Y.
Palacios, H.
Leung, J.W.
Masson, J.Y.
Duijf, P.H.G.
Dray, E.
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Nucleic Acids Research (NAR), 2024; 52(3):1173-1187
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Abstract
Efficient DNA repair and limitation of genome rearrangements rely on crosstalk between different DNA double-strand break (DSB) repair pathways, and their synchronization with the cell cycle. The selection, timing and efficacy of DSB repair pathways are influenced by post-translational modifications of histones and DNA damage repair (DDR) proteins, such as phosphorylation. While the importance of kinases and serine/threonine phosphatases in DDR have been extensively studied, the role of tyrosine phosphatases in DNA repair remains poorly understood. In this study, we have identified EYA4 as the protein phosphatase that dephosphorylates RAD51 on residue Tyr315. Through its Tyr phosphatase activity, EYA4 regulates RAD51 localization, presynaptic filament formation, foci formation, and activity. Thus, it is essential for homologous recombination (HR) at DSBs. DNA binding stimulates EYA4 phosphatase activity. Depletion of EYA4 decreases single-stranded DNA accumulation following DNA damage and impairs HR, while overexpression of EYA4 in cells promotes dephosphorylation and stabilization of RAD51, and thereby nucleoprotein filament formation. Our data have implications for a pathological version of RAD51 in EYA4-overexpressing cancers.
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Data source: Data availability, https://doi.org/10.1093/nar/gkad1177
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Copyright 2023 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License. (https://creativecommons.org/licenses/by-nc/4.0/)