Phosphorylation of the DNA repair scaffold SLX4 drives folding of the SAP domain and activation of the MUS81-EME1 endonuclease.

Autor:	Payliss BJ; Department of Biochemistry, University of Toronto, Toronto, ON M56 1A8, Canada., Tse YWE; Department of Biochemistry, University of Toronto, Toronto, ON M56 1A8, Canada., Reichheld SE; Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Lemak A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Yun HY; Department of Biochemistry, University of Toronto, Toronto, ON M56 1A8, Canada., Houliston S; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Patel A; Department of Biochemistry, University of Toronto, Toronto, ON M56 1A8, Canada., Arrowsmith CH; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada; Structural Genomics Consortium, Toronto, ON M5G 1L7, Canada., Sharpe S; Department of Biochemistry, University of Toronto, Toronto, ON M56 1A8, Canada; Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Wyatt HDM; Department of Biochemistry, University of Toronto, Toronto, ON M56 1A8, Canada; Canada Research Chairs Program, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: haley.wyatt@utoronto.ca.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2022 Oct 25; Vol. 41 (4), pp. 111537.
DOI:	10.1016/j.celrep.2022.111537
Abstrakt:	The DNA repair scaffold SLX4 has multifaceted roles in genome stability, many of which depend on structure-selective endonucleases. SLX4 coordinates the cell cycle-regulated assembly of SLX1, MUS81-EME1, and XPF-ERCC1 into a tri-nuclease complex called SMX. Mechanistically, how the mitotic kinase CDK1 regulates the interaction between SLX4 and MUS81-EME1 remains unclear. Here, we show that CDK1-cyclin B phosphorylates SLX4 residues T1544, T1561, and T1571 in the MUS81-binding region (SLX4 MBR ). Phosphorylated SLX4 MBR relaxes the substrate specificity of MUS81-EME1 and stimulates cleavage of replication and recombination structures, providing a biochemical explanation for the chromosome pulverization that occurs when SLX4 binds MUS81 in S-phase. Remarkably, phosphorylation of SLX4 MBR drives folding of an SAP domain, which underpins the high-affinity interaction with MUS81. We also report the structure of phosphorylated SLX4 MBR and identify the MUS81-binding interface. Our work provides mechanistic insights into how cell cycle-regulated phosphorylation of SLX4 drives the recruitment and activation of MUS81-EME1. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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