Dataset Information

RAD54L2 mediates a novel mechanism to counter TOP2-DNA adducts

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. Anti-cancer agents such as etoposide operate by stabilising TOP2ccs, ultimately generating genotoxic TOP2-DNA protein crosslinks that require processing and repair. Here, we identify RAD54L2 as a factor promoting TOP2cc resolution. We demonstrate that RAD54L2 acts through a novel mechanism together with ZNF451 and independent of TDP2. Our work suggests a model wherein RAD54L2 recognises 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.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Petra Beli

LAB HEAD: Petra Beli

PROVIDER: PXD046611 | Pride | 2024-01-26

REPOSITORIES: Pride

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Publications

RAD54L2 counters TOP2-DNA adducts to promote genome stability.

D'Alessandro Giuseppina G Morales-Juarez David A DA Richards Sean L SL Nitiss Karin C KC Serrano-Benitez Almudena A Wang Juanjuan J Thomas John C JC Gupta Vipul V Voigt Andrea A Belotserkovskaya Rimma R Goh Chen Gang CG Bowden Anne Ramsay AR Galanty Yaron Y Beli Petra P Nitiss John L JL Zagnoli-Vieira Guido G Jackson Stephen P SP

Science advances 20231206 49

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 t ...[more]

PMID: 38055822

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Dataset Information

RAD54L2 mediates a novel mechanism to counter TOP2-DNA adducts

Publications

RAD54L2 counters TOP2-DNA adducts to promote genome stability.

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