Anchorage-independent and faster growth in clonal population from UV-irradiated NER-deficient cells.

Human tumours are characterized by both molecular and functional heterogeneity, which drives cancer cell growth. In this context, the selection of subclones that acquire enhanced proliferative capacity and resistance to pharmacological treatments represents a necessary step in tumour progression. In the presence of DNA damage, efficient signalling and lesion removal are crucial in preventing the accumulation of genomic mutations. In Nucleotide Excision Repair (NER) pathways, the loss of interaction between DDB2 and PCNA (referred to as DDB2PCNA-) results in genomic instability, delayed damage removal and activation of the epithelial-to-mesenchymal transition (EMT) transcriptional program. In this study, we demonstrate that human cellular clones, derived from UV-damaged cells expressing DDB2PCNA-, exhibit behaviours typically associated with tumour heterogeneity. Specifically, these clones show anchorage-independent growth, differences in cell cycle regulation, frequency of atypical mitoses, expression of oncogenes and tumour suppressors and resistance to cisplatin treatment. Taken together, these findings highlight the critical role of DDB2-PCNA interaction in maintaining genome stability and preventing cellular transformation.