RESUMO
RNA editing is a post-transcriptional process that challenges the central dogma of molecular biology by modifying RNA sequences, introducing nucleotide changes at specific sites, and generating functional diversity beyond the genomic code, especially when it concerns organellar transcripts. In plants, this phenomenon is widespread, but its extent varies significantly among species and organellar genomes. Among land plants, the heterosporous lycophytes (i.e., Isoetes and Selaginella) stand out for their exceptionally high numbers of RNA-editing sites, despite their morphological stasis and ancient lineage. In this study, we explore the complete set of organellar protein-coding genes in the aquatic plant group Isoetes, providing a detailed analysis of RNA editing in both the mitochondrial and plastid genomes. Our findings reveal a remarkable abundance of RNA editing, particularly in the mitochondrial genome, with thousands of editing sites identified. Interestingly, the majority of these edits result in non-silent substitutions, suggesting a role in fine-tuning protein structure and function. Furthermore, we observe a consistent trend of increased hydrophobicity in membrane-bound proteins, supporting the notion that RNA editing may confer a selective advantage by preserving gene functionality in Isoetes. The conservation of highly edited RNA sequences over millions of years underscores the evolutionary significance of RNA editing. Additionally, the study sheds light on the dynamic nature of RNA editing, with shared editing sites reflecting common ancestry whereas exclusive edits matching more recent radiation events within the genus. This work advances our understanding of the intricate interplay between RNA editing, adaptation, and evolution in land plants and highlights the unique genomic features of Isoetes, providing a foundation for further investigations into the functional consequences of RNA editing in this enigmatic plant lineage.
RESUMO
PURPOSE: As an epigenetic regulation mechanism after transcription, RNA modification is installed by endogenous "writer" enzymes and is widely involved in a variety of physiological processes, including cancer progression. This study explored the RNA modification patterns of cervical cancer to clarify overall effect of RNA modification on tumor microenvironment (TME) characteristics and immune/targeted therapy. METHODS: 26 RNA modification "writers" were clustered, and the RNA modification patterns and TME characteristics of cervical cancer patients in TCGA were systematically evaluated. Based on differentially expressed genes (DEGs) between different RNA modification patterns, an RNA modification "writer" score (WM score) system was developed to assess the RNA modification of a single sample. RESULTS: Two different RNA modification patterns of cervical cancer were identified, and these patterns were significantly related to the prognosis and TME infiltration characteristics of patients. WM score was an independent risk factor for the prognosis of cervical cancer. High WM score was characterized by poor prognosis, low immune infiltration and low tumor mutation burden (TMB), while low-WM score was related to relatively long overall survival (OS), more immune components in TME and increased TMB. In addition, the low-WM score group was expected to be more sensitive to programmed cell death protein 1 (PD-1) therapy and showed lower predicted IC50 of chemotherapy drugs paclitaxel and cisplatin treatment. CONCLUSIONS: This study identified and characterized RNA modification patterns, and clarified potential relationship between RNA modification patterns and immune infiltration characteristics and immunotherapy of cervical cancer, offering a new evaluation scheme for treatment of cervical cancer patients.
Assuntos
Microambiente Tumoral , Neoplasias do Colo do Útero , Biomarcadores Tumorais/genética , Epigênese Genética , Feminino , Humanos , Prognóstico , RNA/genética , Microambiente Tumoral/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/terapiaRESUMO
N6-methyladenosine (m6A) is the most abundant internal modification described in eukaryotic mRNA and several viral RNA including human respiratory syncytial virus (HRSV). Here, we evaluated the impact of m6A writers, erasers and readers on HRSV genomic RNA accumulation and inclusion bodies assembly during viral replication. We observed that the METTL3/METTL14 m6A writer complex plays a negative role in HRSV protein synthesis and viral titers, while m6A erasers FTO and ALKBH5 had the opposite effect. We also observed that m6A readers YTHDF1-3 bind to the viral genomic RNA inducing a decrease in its intracellular levels and thus, inhibiting viral replication. Finally, we observed that overexpression of YTHDFs proteins caused a decrease in the size of inclusion bodies (IBs), accompanied by an increase in their number. METTL3 knockdown cells showed an opposite effect indicating that the dynamics of IBs assembly and coalescence are strongly affected by m6A readers in a mechanism dependent on m6A writers. Taken together, our results demonstrated that the m6A modification negatively affects HRSV replication, possibly through a mechanism involving the assembly of inclusion bodies, the main factories of viral genomic RNA synthesis.
RESUMO
Methylation of N6-adenosine (m6A) is the most prevalent internal RNA modification and is especially common among the messenger RNAs. These m6A modifications regulate splicing, translocation, stability and translation of RNA through dynamic and reversible interactions with m6A-binding proteins, namely the writers, erasers and readers. RNA methyltransferases catalyze the m6A modifications, while demethylases reverse this methylation. Deregulation of the m6A modification process has been implicated in human carcinogenesis, including melanoma-which carries one of the highest mutant rates. In this review, we provide an up-to-date summary of m6A regulation and its biological impacts on normal and cancer cells, with emphasis on the deregulation of m6A modification and m6A regulators in melanoma. In addition, we highlight the prospective potential of exploiting m6A modification in the treatment of melanoma and non-cancer diseases.
Assuntos
Adenosina/análogos & derivados , Melanoma/metabolismo , Metiltransferases/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/metabolismo , Adenosina/metabolismo , Adenosina/fisiologia , Expressão Gênica , Humanos , Melanoma/genética , Metilação , Metiltransferases/genética , Mutação , Oxirredutases N-Desmetilantes/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Fatores de Processamento de RNA/metabolismo , Neoplasias Cutâneas/genéticaRESUMO
Trypanosoma and Leishmania parasites cause devastating tropical diseases resulting in serious global health consequences. These organisms have complex life cycles with mammalian hosts and insect vectors. The parasites must, therefore, survive in different environments, demanding rapid physiological and metabolic changes. These responses depend upon regulation of gene expression, which primarily occurs posttranscriptionally. Altering the composition or conformation of RNA through nucleotide modifications is one posttranscriptional mechanism of regulating RNA fate and function, and modifications including N6-methyladenosine (m6A), N1-methyladenosine (m1A), N5-methylcytidine (m5C), N4-acetylcytidine (ac4C), and pseudouridine (Ψ), dynamically regulate RNA stability and translation in diverse organisms. Little is known about RNA modifications and their machinery in Trypanosomatids, but we hypothesize that they regulate parasite gene expression and are vital for survival. Here, we identified Trypanosomatid homologs for writers of m1A, m5C, ac4C, and Ψ and analyze their evolutionary relationships. We systematically review the evidence for their functions and assess their potential use as therapeutic targets. This work provides new insights into the roles of these proteins in Trypanosomatid parasite biology and treatment of the diseases they cause and illustrates that Trypanosomatids provide an excellent model system to study RNA modifications, their molecular, cellular, and biological consequences, and their regulation and interplay.