RESUMO
5-Methyl-2'-deoxycytidine (mC) at CpG sites plays a key role in the epigenetic gene regulation, cell differentiation, and carcinogenesis. Despite the importance of mC for normal cell function, CpG dinucleotides are known as mutagenesis hotspots. Deamination of mC yields T, causing CâT transitions. However, several recent studies demonstrated the effect of epigenetic modifications of C on the fidelity and efficiency of DNA polymerases and excision repair enzymes. The review summarizes the available data that indicate the existence of deamination-independent mechanisms of mutagenesis at CpG sites.
Assuntos
Reparo do DNA , Epigênese Genética , Humanos , Ilhas de CpG , Mutagênese , Reparo do DNA/genética , Carcinogênese , Metilação de DNARESUMO
5-Methyl-2'-deoxycytidine (mC) and the product of its controlled oxidation, 5-hydroxymethyl-2'-cytidine (hmC), play a key role in the epigenetic regulation of gene expression, the cell differentiation, and the carcinogenesis. Due to spontaneious deamination, genomic CpG sites containing mC and hmC serve as mutagenesis hotspots. In addition, error-prone translesion and reparative DNA polymerases may serve as additional source of mutations in the lesion-containing regions with CpG sites. In the present work, we performed in vitro analysis of the accuracy of nucleotide incorporation opposite to mC and hmC by human DNA polymerases Polß, Polλ, Polη, Polι, PoIκ and primase polymerase PrimPol. The results of the study show a high accuracy of copying mC and hmC by the reparative DNA polymerases polymerases Polß and Polλ, while Polη, Polι, PoIκ, and PrimPol copied mC and hmC with less accuracy evident by incorporation of dAMP and dTMP. The same spectrum of error-prone dNMP incorporation was also noted at sites with unmodified cytosines.
Assuntos
DNA Polimerase Dirigida por DNA , Epigênese Genética , DNA Primase , DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Desoxicitidina/análogos & derivados , Humanos , Enzimas MultifuncionaisRESUMO
Many chemotherapy drugs block tumor cell division by damaging DNA. DNA polymerases eta (Pol η), iota (Pol ι), kappa (Pol κ), REV1 of the Y-family and zeta (Pol ζ) of the B-family efficiently incorporate nucleotides opposite a number of DNA lesions during translesion DNA synthesis. Primase-polymerase PrimPol and the Pol α-primase complex reinitiate DNA synthesis downstream of the damaged sites using their DNA primase activity. These enzymes can decrease the efficacy of chemotherapy drugs, contribute to the survival of tumor cells and to the progression of malignant diseases. DNA polymerases are promising targets for increasing the effectiveness of chemotherapy, and mutations and polymorphisms in some DNA polymerases can serve as additional prognostic markers in a number of oncological disorders.
Assuntos
Antineoplásicos/farmacologia , DNA Polimerase Dirigida por DNA/metabolismo , DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Inibidores da Síntese de Ácido Nucleico/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , DNA Polimerase Dirigida por DNA/genética , Humanos , Neoplasias/tratamento farmacológico , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Polimorfismo GenéticoRESUMO
Tens of thousands of DNA lesions are formed in mammalian cells each day. DNA translesion synthesis is the main mechanism of cell defense against unrepaired DNA lesions. DNA polymerases iota (Pol ι), eta (Pol η), kappa (Pol κ), and zeta (Pol ζ) have active sites that are less stringent toward the DNA template structure and efficiently incorporate nucleotides opposite DNA lesions. However, these polymerases display low accuracy of DNA synthesis and can introduce mutations in genomic DNA. Impaired functioning of these enzymes can lead to an increased risk of cancer.
