Long-term, genome-wide kinetic analysis of the effect of the circadian clock and transcription on the repair of cisplatin-DNA adducts in the mouse liver

Jun 21, 2019The Journal of biological chemistry

How the body clock and gene activity affect DNA repair of cisplatin damage in mouse liver over time

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Abstract

Cisplatin-induced DNA damage repair is nearly complete for transcribed strands after 2 days, while nontranscribed strands require weeks.

Repair of cisplatin-DNA adducts is controlled by two circadian programs in mice.
The circadian clock influences the transcription of 2000 genes, affecting repair of the transcribed strand in a rhythmic manner.
A single phase of excision repair activity is regulated by the circadian clock for nontranscribed strands and the rest of the genome.
Transcription-driven repair shows rhythmic patterns in gene expression up to 2 days post-cisplatin injection.
A trend in repair efficiency is observed from the 5' to 3' end of expressed genes over time.

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Cisplatin is the most commonly used chemotherapeutic drug for managing solid tumors. However, toxicity and the innate or acquired resistance of cancer cells to the drug limit its usefulness. Cisplatin kills cells by forming cisplatin-DNA adducts, most commonly the Pt-d(GpG) diadduct. We recently showed that, in mice, repair of this adduct 2 h following injection is controlled by two circadian programs. 1) The circadian clock controls transcription of 2000 genes in liver and, via transcription-directed repair, controls repair of the transcribed strand (TS) of these genes in a rhythmic fashion unique to each gene's phase of transcription. 2) The excision repair activity itself is controlled by the circadian clock with a single phase at which the repair of the nontranscribed strand (NTS) and the rest of the genome takes place. Here, we followed the repair kinetic for long periods genome-wide both globally and at single nucleotide resolution by the Excision Repair-sequencing (XR-seq) method to better understand cisplatin DNA damage and repair. We find that transcription-driven repair is nearly complete after 2 days, whereas weeks are required for repair of the NTS and the rest of the genome. TS repair oscillates in rhythmically expressed genes up to 2 days post injection, and in all expressed genes, we see a trend in TS repair with time from the 5' to 3' end. These findings help to understand the circadian- and transcription-dependent and -independent control of repair in response to cisplatin, and should aid in designing cisplatin chemotherapy regimens with improved therapeutic indexes.

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Long-term, genome-wide kinetic analysis of the effect of the circadian clock and transcription on the repair of cisplatin-DNA adducts in the mouse liver

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