RESUMO
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.
Assuntos
Dano ao DNA , Reparo do DNA , Replicação do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Neoplasias/patologia , Animais , Humanos , Neoplasias/genética , Neoplasias/metabolismo , DNA Polimerase iotaRESUMO
Proteins of the Piwi family and short Piwi-interacting RNAs (piRNAs) ensure the protection of the genome from transposable elements. We have previously shown that nuclear Piwi protein tends to concentrate in the nucleoli of the cells of Drosophila melanogaster ovaries. It could be hypothesized that the function of Piwi in the nucleolus is associated with the repression of R1 and R2 retrotransposons inserted into the rDNA cluster. Here, we show that Piwi participates in recruiting Udd protein to nucleoli. Udd is a component of the conserved Selectivity Factor I-like (SL1-like) complex, which is required for transcription initiation by RNA polymerase I. We found that Udd localization depends on Piwi in germline cells, but not in somatic cells of the ovaries. In contrast, knockdowns of the SL1-like components (Udd or TAF1b) do not disrupt Piwi localization. We also observed that the absence of Udd or TAF1b in germline cells, as well as the impairment of Piwi nuclear localization lead to the accumulation of late stage egg chambers in the ovaries, which could be explained by reduced rRNA transcription. These results allow us to propose for the first time a role for Piwi in the nucleolus that is not directly associated with transposable element repression.
Assuntos
Nucléolo Celular/metabolismo , RNA Polimerase I/metabolismo , RNA Interferente Pequeno/metabolismo , Iniciação da Transcrição Genética/fisiologia , Animais , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Nucléolo Celular/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , RNA Polimerase I/genética , RNA Interferente Pequeno/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
In this review we consider the role of the piRNA system in transposable element silencing in the Drosophila melanogaster germline. We focus on new data that demonstrate the mechanisms of initiation of piRNA biogenesis in ovarian germinal cells and the role of Piwi protein in this process, including our own results.
Assuntos
Elementos de DNA Transponíveis/fisiologia , Inativação Gênica/fisiologia , Ovário/metabolismo , Óvulo/metabolismo , Animais , Drosophila melanogaster , FemininoRESUMO
Short (25-35 nucleotides) regulatory piPHK, along with RNA-binding proteins of the Piwi family, constitute an evolutionarily conserved system that functions mainly in eukaryotic gonads. The system can be regarded as a variant of the mechanism of RNA interference, which is based on the recognition of target RNA as a result of complementary interactions with piRNA. The variants of this regulatory system function in the germline cells, including stem cells and somatic cells of the niche, ensuring maintenance of the germline stem cells and their differentiation. One of the most important functions (but not the only one) of this system is the repression of transposons, which guarantees genome stability in germline cells. This review focuses on the works of the authors of the review in the context of outstanding international achievements in a rapidly evolving re- search area, the biology of piRNA and the function of the Piwi protein.
