The accurate bypass of pyrimidine dimers by DNA polymerase eta contributes to ultraviolet-induced mutagenesis

Autor(es)

Menck, C. F. M. ; Galhardo, R. S. ; Quinet, A.

• Tipo de documento: Artigo Científico
• Fonte: MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS; v. 828, p. 10-pg., 2023-11-18.

Resumo

Human xeroderma pigmentosum variant (XP-V) patients are mutated in the POLH gene, responsible for encoding the translesion synthesis (TLS) DNA polymerase eta (Pol eta). These patients suffer from a high frequency of skin tumors. Despite several decades of research, studies on Pol eta still offer an intriguing paradox: How does this error-prone polymerase suppress mutations? This review examines recent evidence suggesting that cyclobutane pyrimidine dimers (CPDs) are instructional for Pol eta. Consequently, it can accurately replicate these lesions, and the mutagenic effects induced by UV radiation stem from the deamination of C-containing CPDs. In this model, the deamination of C (forming a U) within CPDs leads to the correct insertion of an A opposite to the deaminated C (or U)-containing dimers. This intricate process results in C>T transitions, which represent the most prevalent mutations detected in skin cancers. Finally, the delayed replication in XP-V cells amplifies the process of C-deamination in CPDs and increases the burden of C>T mutations prevalent in XP-V tumors through the activity of backup TLS polymerases. (AU)

• Processo FAPESP: 21/15170-5 - Elementos conjugativos e integrativos da família SXT/R391 em Proteus mirabilis
• Beneficiário: Rodrigo da Silva Galhardo
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/19435-3 - Papel de danos no DNA e função mitocondrial em envelhecimento vascular, imune e neurológico (DNA MoVINg)
• Beneficiário: Carlos Frederico Martins Menck
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs