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RAD54L2 counters TOP2-DNA adducts to promote genome stability.
D'Alessandro, Giuseppina; Morales-Juarez, David A; Richards, Sean L; Nitiss, Karin C; Serrano-Benitez, Almudena; Wang, Juanjuan; Thomas, John C; Gupta, Vipul; Voigt, Andrea; Belotserkovskaya, Rimma; Goh, Chen Gang; Bowden, Anne Ramsay; Galanty, Yaron; Beli, Petra; Nitiss, John L; Zagnoli-Vieira, Guido; Jackson, Stephen P.
Afiliação
  • D'Alessandro G; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Morales-Juarez DA; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • Richards SL; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • Nitiss KC; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Serrano-Benitez A; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • Wang J; UIC College of Pharmacy, Rockford, IL, USA.
  • Thomas JC; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Gupta V; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • Voigt A; Institute of Molecular Biology (IMB), Chromatin Biology & Proteomics, Mainz, Germany.
  • Belotserkovskaya R; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • Goh CG; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • Bowden AR; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Galanty Y; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • Beli P; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Nitiss JL; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • Zagnoli-Vieira G; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Jackson SP; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
Sci Adv ; 9(49): eadl2108, 2023 12 08.
Article em En | MEDLINE | ID: mdl-38055822
ABSTRACT
The catalytic cycle of topoisomerase 2 (TOP2) enzymes proceeds via a transient DNA double-strand break (DSB) intermediate termed the TOP2 cleavage complex (TOP2cc), in which the TOP2 protein is covalently bound to DNA. Anticancer agents such as etoposide operate by stabilizing TOP2ccs, ultimately generating genotoxic TOP2-DNA protein cross-links that require processing and repair. Here, we identify RAD54 like 2 (RAD54L2) as a factor promoting TOP2cc resolution. We demonstrate that RAD54L2 acts through a novel mechanism together with zinc finger protein associated with tyrosyl-DNA phosphodiesterase 2 (TDP2) and TOP2 (ZATT/ZNF451) and independent of TDP2. Our work suggests a model wherein RAD54L2 recognizes sumoylated TOP2 and, using its ATPase activity, promotes TOP2cc resolution and prevents DSB exposure. These findings suggest RAD54L2-mediated TOP2cc resolution as a potential mechanism for cancer therapy resistance and highlight RAD54L2 as an attractive candidate for drug discovery.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Adutos de DNA / Proteínas de Ligação a DNA Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Adutos de DNA / Proteínas de Ligação a DNA Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article