Base and nucleotide excision repair facilitate resolution of platinum drugs-induced transcription blockage

Jana Slyskova, Mariangela Sabatella, Cristina Ribeiro-Silva, Colin Stok, Arjan F. Theil, Wim Vermeulen, Hannes Lans*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    46 Citations (Scopus)
    198 Downloads (Pure)

    Abstract

    Sensitivity and resistance of cells to platinum drug chemotherapy are to a large extent determined by activity of the DNA damage response (DDR). Combining chemotherapy with inhibition of specific DDR pathways could therefore improve treatment efficacy. Multiple DDR pathways have been implicated in removal of platinum-DNA lesions, but it is unclear which exact pathways are most important to cellular platinum drug resistance. Here, we used CRISPR/Cas9 screening to identify DDR proteins that protect colorectal cancer cells against the clinically applied platinum drug oxaliplatin. We find that besides the expected homologous recombination, Fanconi anemia and translesion synthesis pathways, in particular also transcription-coupled nucleotide excision repair (TC-NER) and base excision repair (BER) protect against platinum-induced cytotoxicity. Both repair pathways are required to overcome oxaliplatin-and cisplatin-induced transcription arrest. In addition to the generation of DNA crosslinks, exposure to platinum drugs leads to reactive oxygen species production that induces oxidative DNA lesions, explaining the requirement for BER. Our findings highlight the importance of transcriptional integrity in cells exposed to platinum drugs and suggest that both TC-NER and BER should be considered as targets for novel combinatorial treatment strategies.

    Original languageEnglish
    Pages (from-to)9537-9549
    Number of pages13
    JournalNucleic Acids Research
    Volume46
    Issue number18
    DOIs
    Publication statusPublished - 12-Oct-2018

    Keywords

    • INTERSTRAND CROSS-LINKS
    • RNA-POLYMERASE-II
    • XERODERMA-PIGMENTOSUM
    • COUPLED REPAIR
    • LIGASE-III
    • DNA-REPAIR
    • SUPEROXIDE ANION
    • CISPLATIN
    • DAMAGE
    • PROTEIN

    Cite this