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Cisplatin-DNA adduct repair of transcribed genes is controlled by two circadian programs in mouse tissues

Significance Cisplatin is a front-line drug in treatment of most solid tissue cancers. It kills cancer cells by damaging their DNA. Although it is quite effective it has two major drawbacks. First, it has serious side effects, including nephrotoxicity, hepatotoxicity, and neurotoxicity. Secondly, some cancers exhibit primary or acquired resistance to the drug which limit its usefulness. Attempts have been made to administer the drug at certain times of the day (chronochemotherapy) to overcome these limitations but these attempts have had very limited success. Here, we generate genome-wide and at single-nucleotide-resolution circadian DNA repair maps for mouse kidney and liver with the ultimate goal of developing a rational cisplatin chronochemotherapy regimen. Cisplatin is a major cancer chemotherapeutic drug. It kills cancer cells by damaging their DNA, mainly in the form of Pt-d(GpG) diadducts. However, it also has serious side effects, including nephrotoxicity and hepatotoxicity that limit its usefulness. Chronotherapy is taking circadian time into account during therapy to improve the therapeutic index, by improving efficacy and/or limiting toxicity. To this end, we tested the impact of clock time on excision repair of cisplatin-induced DNA damage at single-nucleotide resolution across the genome in mouse kidney and liver. We found that genome repair is controlled by two circadian programs. Repair of the transcribed strand (TS) of active, circadian-controlled genes is dictated by each gene’s phase of transcription, which falls across the circadian cycle with prominent peaks at dawn and dusk. In contrast, repair of the nontranscribed strand (NTS) of all genes, repair of intergenic DNA, and global repair overall peaks at Zeitgeber time ZT08, as basal repair capacity, which is controlled by the circadian clock, peaks at this circadian time. Consequently, the TS and NTS of many genes are repaired out of phase. As most cancers are thought to have defective circadian rhythms, these results suggest that future research on timed dosage of cisplatin could potentially reduce damage to healthy tissue and improve its therapeutic index.