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

May 9, 2018Proceedings of the National Academy of Sciences of the United States of America

Repair of DNA damage in active genes follows two daily biological clocks in mouse tissues

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Abstract

Repair of DNA damage from cisplatin peaks at specific times in the circadian cycle.

DNA repair in mouse kidney and liver is regulated by two circadian programs.
Repair of active genes occurs at dawn and dusk, linked to their transcription phase.
The overall capacity for DNA repair peaks at Zeitgeber time ZT08, controlled by the circadian clock.
The transcribed and nontranscribed strands of many genes are repaired at different times.
These findings may inform future strategies for timing cisplatin administration to minimize toxicity.

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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.

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

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