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The toposiomerase IIIalpha-RMI1-RMI2 complex orients human Bloom’s syndrome helicase for efficient disruption of D-loops

Gábor M. Harami (), János Pálinkás, Yeonee Seol, Zoltán J. Kovács, Máté Gyimesi, Hajnalka Harami-Papp, Keir C. Neuman and Mihály Kovács ()
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Gábor M. Harami: Eötvös Loránd University
János Pálinkás: Eötvös Loránd University
Yeonee Seol: National Institutes of Health
Zoltán J. Kovács: Eötvös Loránd University
Máté Gyimesi: Eötvös Loránd University
Hajnalka Harami-Papp: Eötvös Loránd University
Keir C. Neuman: National Institutes of Health
Mihály Kovács: Eötvös Loránd University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Homologous recombination (HR) is a ubiquitous and efficient process that serves the repair of severe forms of DNA damage and the generation of genetic diversity during meiosis. HR can proceed via multiple pathways with different outcomes that may aid or impair genome stability and faithful inheritance, underscoring the importance of HR quality control. Human Bloom’s syndrome (BLM, RecQ family) helicase plays central roles in HR pathway selection and quality control via unexplored molecular mechanisms. Here we show that BLM’s multi-domain structural architecture supports a balance between stabilization and disruption of displacement loops (D-loops), early HR intermediates that are key targets for HR regulation. We find that this balance is markedly shifted toward efficient D-loop disruption by the presence of BLM’s interaction partners Topoisomerase IIIα-RMI1-RMI2, which have been shown to be involved in multiple steps of HR-based DNA repair. Our results point to a mechanism whereby BLM can differentially process D-loops and support HR control depending on cellular regulatory mechanisms.

Date: 2022
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DOI: 10.1038/s41467-022-28208-9

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