Mutagenicity Profile Induced by UVB Light in Human Xeroderma Pigmentosum Group C Cells

• Published in: Photochemistry and photobiology 2022-05, Vol.98 (3), p.713-731
• Main Authors: Quintero‐Ruiz, Nathalia, Corradi, Camila, Moreno, Natália Cestari, Souza, Tiago Antonio, Castro, Ligia, Rocha, Clarissa Ribeiro Reily, Menck, Carlos Frederico Martins
• Format: Article
• Language: English
• Subjects: C cells; Cancer; DNA Damage; DNA Repair; Fibroblasts; Genomes; Humans; Irradiation; Mutagenesis; Mutagenicity; Mutagens; Mutation; Nucleotide excision repair; Nucleotides; Skin; Skin cancer; Skin Neoplasms - genetics; Tumors; Ultraviolet Rays - adverse effects; Xeroderma pigmentosum; Xeroderma Pigmentosum - complications; Xeroderma Pigmentosum - genetics
• ISSN: 0031-8655; 1751-1097
• DOI: 10.1111/php.13516

Nucleotide excision repair (NER) is one of the main pathways for genome protection against structural DNA damage caused by sunlight, which in turn is extensively related to skin cancer development. The mutation spectra induced by UVB were investigated by whole‐exome sequencing of randomly selected clones of NER‐proficient and XP‐C‐deficient human skin fibroblasts. As a model, a cell line unable to recognize and remove lesions (XP‐C) was used and compared to the complemented isogenic control (COMP). As expected, a significant increase of mutagenesis was observed in irradiated XP‐C cells, mainly C>T transitions, but also CC>TT and C>A base substitutions. Remarkably, the C>T mutations occur mainly at the second base of dipyrimidine sites in pyrimidine‐rich sequence contexts, with 5′TC sequence the most mutated. Although T>N mutations were also significantly increased, they were not directly related to pyrimidine dimers. Moreover, the large‐scale study of a single UVB irradiation on XP‐C cells allowed recovering the typical mutation spectrum found in human skin cancer tumors. Eventually, the data may be used for comparison with the mutational profiles of skin tumors obtained from XP‐C patients and may help to understand the mutational process in nonaffected individuals. The mutation spectra induced by UVB light were investigated by whole‐exome sequencing of XP‐C cells, which are deficient in the NER repair pathway. The C>T transitions targeted at the second base of dipyrimidine sites were the most common mutation. Followed by C>A transversions targeted to both oxidized bases or pyrimidine dimers, and T>N mutations which were not targeted to dimers. Additionally, the large‐scale study allowed to recover on the UV‐B irradiated XP‐C cells the typical mutation spectrum of human skin cancer.