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Detection of oxaliplatin- and cisplatin-DNA lesions requires different global genome repair mechanisms that affect their clinical efficacy

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Title
Detection of oxaliplatin- and cisplatin-DNA lesions requires different global genome repair mechanisms that affect their clinical efficacy
Author(s)
Slyskova, Jana; Muniesa-Vargas, Alba; Da Silva, Israel Tojal; Drummond, Rodrigo; Jiyeong Park; Häckes, David; Poetsch, Isabella; Ribeiro-Silva, Cristina; Moretton, Amandine; Heffeter, Petra; Orlando D Schärer; Vermeulen, Wim; Lans, Hannes; Loizou, Joanna I
Publication Date
2023-12
Journal
NAR Cancer, v.5, no.4
Publisher
Oxford University Press
Abstract
The therapeutic efficacy of cisplatin and oxaliplatin depends on the balance between the DNA damage induction and the DNA damage response of tumor cells. Based on clinical evidence, oxaliplatin is administered to cisplatin-unresponsive cancers, but the underlying molecular causes for this tumor specificity are not clear. Hence, stratification of patients based on DNA repair profiling is not sufficiently utilized for treatment selection. Using a combination of genetic, transcriptomics and imaging approaches, we identified factors that promote global genome nucleotide excision repair (GG-NER) of DNA-platinum adducts induced by oxaliplatin, but not by cisplatin. We show that oxaliplatin-DNA lesions are a poor substrate for GG-NER initiating factor XPC and that DDB2 and HMGA2 are required for efficient binding of XPC to oxaliplatin lesions and subsequent GG-NER initiation. Loss of DDB2 and HMGA2 therefore leads to hypersensitivity to oxaliplatin but not to cisplatin. As a result, low DDB2 levels in different colon cancer cells are associated with GG-NER deficiency and oxaliplatin hypersensitivity. Finally, we show that colon cancer patients with low DDB2 levels have a better prognosis after oxaliplatin treatment than patients with high DDB2 expression. We therefore propose that DDB2 is a promising predictive marker of oxaliplatin treatment efficiency in colon cancer. © 2023 The Author(s). Published by Oxford University Press on behalf of NAR Cancer.
URI
https://pr.ibs.re.kr/handle/8788114/14392
DOI
10.1093/narcan/zcad057
ISSN
2632-8674
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > 1. Journal Papers (저널논문)
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