Genomic adaptation and mutational patterns in a HaCaT subline resistant to alkylating agents and ionizing radiation [Hi-C]

In this study, we compared the genomic landscape of resistant cell line HaCaT/SM to its progenitor HaCaT in order to gain insights into genetic changes associated with continuous alkylation and oxidative stress. We established chromosome numbers by cytogenetics, analyzed DNA copy number changes by means of array CGH, employed the genome-wide chromosome conformation capture technique Hi-C to detect chromosomal translocations and defined mutational signatures based on whole genome sequencing data. We observed the SM-associated elimination of the initially prevailing hypotetraploid cell population in favor of a hyperdiploid one, which contrasts with previous observations that link polyploidization to increased tolerance and adaptability towards genotoxic stress. Furthermore, we observed an accumulation of chromosomal translocations, frequently flanked by DNA copy number changes, which indicates a high rate of DNA double strand break misrepair. HaCaT/SM-specific single nucleotide variants showed enrichment of C>A and T>A transversions and a lower rate of deaminated cytosines in the CpG dinucleotide context. Given the frequent use of HaCaT in toxicology this study provides a valuable data source with respect to the original genotype of HaCaT and the mutational signatures associated with chronic alkylation and oxidative stress. Analysis of chromosome numbers by cytogenetic, DNA copy number changes by means of array CGH, chromosomal translocations by Hi-C and mutational signatures by means of whole genome sequencing in the sulfur mustard-resistant cell line HaCaT. *** Submitter declares raw data are unavailable due to privacy issues.