Switch-like phosphorylation of WRN integrates end-resection with RAD51 metabolism at collapsed replication forks.

Autor:	Palermo V; Department of Environment and Health, Mechanisms, Biomarkers and Models Section, Genome Stability Group, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy., Malacaria E; Department of Environment and Health, Mechanisms, Biomarkers and Models Section, Genome Stability Group, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy., Semproni M; Department of Environment and Health, Mechanisms, Biomarkers and Models Section, Genome Stability Group, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy., Camerini S; FAST, Core Facilities Service, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy., Casella M; FAST, Core Facilities Service, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy., Perdichizzi B; Department of Environment and Health, Mechanisms, Biomarkers and Models Section, Genome Stability Group, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy., Valenzisi P; Department of Environment and Health, Mechanisms, Biomarkers and Models Section, Genome Stability Group, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy., Sanchez M; FAST, Core Facilities Service, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy., Marini F; Department of Biosciences, Genomic Instability and Human Pathologies Section, Università degli Studi di Milano, Via Giovanni Celoria 26, 20133 Milan, Italy., Pellicioli A; Department of Biosciences, Genomic Instability and Human Pathologies Section, Università degli Studi di Milano, Via Giovanni Celoria 26, 20133 Milan, Italy., Franchitto A; Department of Environment and Health, Mechanisms, Biomarkers and Models Section, Genome Stability Group, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy., Pichierri P; Department of Environment and Health, Mechanisms, Biomarkers and Models Section, Genome Stability Group, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.; Istituto Nazionale di Biostrutture e Biosistemi, Viale delle Medaglie d'Oro 305, 00134 Rome, Italy.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2024 Nov 11; Vol. 52 (20), pp. 12334-12350.
DOI:	10.1093/nar/gkae807
Abstrakt:	Replication-dependent DNA double-strand breaks are harmful lesions preferentially repaired by homologous recombination (HR), a process that requires processing of DNA ends to allow RAD51-mediated strand invasion. End resection and subsequent repair are two intertwined processes, but the mechanism underlying their execution is still poorly appreciated. The WRN helicase is one of the crucial factors for end resection and is instrumental in selecting the proper repair pathway. Here, we reveal that ordered phosphorylation of WRN by the CDK1, ATM and ATR kinases defines a complex regulatory layer essential for correct long-range end resection, connecting it to repair by HR. We establish that long-range end resection requires an ATM-dependent phosphorylation of WRN at Ser1058 and that phosphorylation at Ser1141, together with dephosphorylation at the CDK1 site Ser1133, is needed for the proper metabolism of RAD51 foci and RAD51-dependent repair. Collectively, our findings suggest that regulation of WRN by multiple kinases functions as a molecular switch to allow timely execution of end resection and repair at replication-dependent DNA double-strand breaks. (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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