Cancer cells that survive checkpoint adaptation (mitosis with damaged DNA) aquire major chromosomal rearrangements

Abstract

We investigated the relationship between checkpoint adaptation and chromosomal change in human cancer cells. HT-29 and M059K cells treated with pharmacological concentrations of camptothecin acquired damaged DNA, overcame the DNA damage checkpoint and entered mitosis with damaged DNA, a phenomenon named checkpoint adaptation. We observed that cells that survived checkpoint adaptation acquired major chromosomal rearrangements. Surviving cells had fewer chromosomes and increased numbers of interchromosomal rearrangements per cell, compared to cells that did not undergo checkpoint adaptation. We investigated whether the DNA repair enzyme polynucleotide kinase 3’-phosphatase (PNKP) participates in checkpoint adaptation by using the PNKP inhibitor A12B4C50. We showed that A12B4C50 reduced the interaction between the DNA repair complex PNKP-XRCC1 in cells; however, no effect on checkpoint adaptation was observed. Future studies would need to focus on DNA repair pathways that may reduce the chromosomal change caused by checkpoint adaptation. This can provide insight into the biology of genotoxic treatments used in cancer patients.