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Molecular Cell Jun 2022Information in mRNA has largely been thought to be confined to its nucleotide sequence. However, the advent of mapping techniques to detect modified nucleotides has... (Review)
Review
Information in mRNA has largely been thought to be confined to its nucleotide sequence. However, the advent of mapping techniques to detect modified nucleotides has revealed that mRNA contains additional information in the form of chemical modifications. The most abundant modified nucleotide is N-methyladenosine (mA), a methyl modification of adenosine. Although early studies viewed mA as a dynamic and tissue-specific modification, it is now clear that the mRNAs that contain mA and the location of mA in those transcripts are largely universal and are influenced by gene architecture, i.e., the size and location of exons and introns. mA can affect nuclear processes such as splicing and epigenetic regulation, but the major effect of mA on mRNAs is to promote degradation in the cytoplasm. mA marks a functionally related cohort of mRNAs linked to certain biological processes, including cell differentiation and cell fate determination. mA is also enriched in other cohorts of mRNAs and can therefore affect their respective cellular processes and pathways. Future work will focus on understanding how the mA pathway is regulated to achieve control of mA-containing mRNAs.
Topics: Adenosine; Epigenesis, Genetic; Gene Expression; Humans; Methyltransferases; Nucleotides; RNA, Messenger
PubMed: 35714585
DOI: 10.1016/j.molcel.2022.05.029 -
Cell Jun 2020N-methyladenosine (mA) is the most abundant mRNA nucleotide modification and regulates critical aspects of cellular physiology and differentiation. mA is thought to...
N-methyladenosine (mA) is the most abundant mRNA nucleotide modification and regulates critical aspects of cellular physiology and differentiation. mA is thought to mediate its effects through a complex network of interactions between different mA sites and three functionally distinct cytoplasmic YTHDF mA-binding proteins (DF1, DF2, and DF3). In contrast to the prevailing model, we show that DF proteins bind the same mA-modified mRNAs rather than different mRNAs. Furthermore, we find that DF proteins do not induce translation in HeLa cells. Instead, the DF paralogs act redundantly to mediate mRNA degradation and cellular differentiation. The ability of DF proteins to regulate stability and differentiation becomes evident only when all three DF paralogs are depleted simultaneously. Our study reveals a unified model of mA function in which all mA-modified mRNAs are subjected to the combined action of YTHDF proteins in proportion to the number of mA sites.
Topics: Adenosine; Cell Differentiation; HeLa Cells; Humans; Methylation; Methyltransferases; Protein Biosynthesis; RNA Stability; RNA, Messenger; RNA-Binding Proteins
PubMed: 32492408
DOI: 10.1016/j.cell.2020.05.012 -
International Journal of Molecular... Dec 2020N6‑methyladenosine (m6A) is the most prevalent and abundant type of internal post‑transcriptional RNA modification in eukaryotic cells. Multiple types of RNA,... (Review)
Review
N6‑methyladenosine (m6A) is the most prevalent and abundant type of internal post‑transcriptional RNA modification in eukaryotic cells. Multiple types of RNA, including mRNAs, rRNAs, tRNAs, long non‑coding RNAs and microRNAs, are involved in m6A methylation. The biological function of m6A modification is dynamically and reversibly mediated by methyltransferases (writers), demethylases (erasers) and m6A binding proteins (readers). The methyltransferase complex is responsible for the catalyzation of m6A modification and is typically made up of methyltransferase‑like (METTL)3, METTL14 and Wilms tumor 1‑associated protein. Erasers remove methylation by fat mass and obesity‑associated protein and ALKB homolog 5. Readers play a role through the recognition of m6A‑modified targeted RNA. The YT521‑B homology domain family, heterogeneous nuclear ribonucleoprotein and insulin‑like growth factor 2 mRNA‑binding protein serve as m6A readers. The m6A methylation on transcripts plays a pivotal role in the regulation of downstream molecular events and biological functions, such as RNA splicing, transport, stability and translatability at the post‑transcriptional level. The dysregulation of m6A modification is associated with cancer, drug resistance, virus replication and the pluripotency of embryonic stem cells. Recently, a number of studies have identified aberrant m6A methylation in cardiovascular diseases (CVDs), including cardiac hypertrophy, heart failure, arterial aneurysm, vascular calcification and pulmonary hypertension. The aim of the present review article was to summarize the recent research progress on the role of m6A modification in CVD and give a brief perspective on its prospective applications in CVD.
Topics: Adenosine; Animals; Cardiovascular Diseases; Humans; Methylation; Polymorphism, Single Nucleotide; RNA; RNA-Binding Proteins
PubMed: 33125109
DOI: 10.3892/ijmm.2020.4746 -
Molecular Cancer Jul 2022The resistance of tumor cells to therapy severely impairs the efficacy of treatment, leading to recurrence and metastasis of various cancers. Clarifying the underlying... (Review)
Review
The resistance of tumor cells to therapy severely impairs the efficacy of treatment, leading to recurrence and metastasis of various cancers. Clarifying the underlying mechanisms of therapeutic resistance may provide new strategies for overcoming cancer resistance. N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotes, and is involved in the regulation of RNA splicing, translation, transport, degradation, stability and processing, thus affecting several physiological processes and cancer progression. As a novel type of multifunctional non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have been demonstrated to play vital roles in anticancer therapy. Currently, accumulating studies have revealed the mutual regulation of m6A modification and circRNAs, and their interaction can further influence the sensitivity of cancer treatment. In this review, we mainly summarized the recent advances of m6A modification and circRNAs in the modulation of cancer therapeutic resistance, as well as their interplay and potential mechanisms, providing promising insights and future directions in reversal of therapeutic resistance in cancer.
Topics: Adenosine; Drug Resistance, Neoplasm; Humans; Methylation; Neoplasms; RNA, Circular
PubMed: 35843942
DOI: 10.1186/s12943-022-01620-x -
Molecular Cancer Jan 2021RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding... (Review)
Review
RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N-methyladenosine (mA), 5-methylcytosine (mC) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.
Topics: 5-Methylcytosine; Adenosine; Humans; Neoplasms; Pseudouridine; RNA; RNA Processing, Post-Transcriptional
PubMed: 33461542
DOI: 10.1186/s12943-020-01263-w -
Journal of Hematology & Oncology Jan 2022RNA demethylase ALKBH5 takes part in the modulation of N-methyladenosine (mA) modification and controls various cell processes. ALKBH5-mediated mA demethylation... (Review)
Review
RNA demethylase ALKBH5 takes part in the modulation of N-methyladenosine (mA) modification and controls various cell processes. ALKBH5-mediated mA demethylation regulates gene expression by affecting multiple events in RNA metabolism, e.g., pre-mRNA processing, mRNA decay and translation. Mounting evidence shows that ALKBH5 plays critical roles in a variety of human malignancies, mostly via post-transcriptional regulation of oncogenes or tumor suppressors in an mA-dependent manner. Meanwhile, increasing non-coding RNAs are recognized as functional targets of ALKBH5 in cancers. Here we reviewed up-to-date findings about the pathological roles of ALKBH5 in cancer, the molecular mechanisms by which it exerts its functions, as well as the underlying mechanism of its dysregulation. We also discussed the therapeutic implications of targeting ALKBH5 in cancer and potential ALKBH5-targeting strategies.
Topics: Adenosine; AlkB Homolog 5, RNA Demethylase; Animals; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Models, Molecular; Neoplasms; RNA; RNA Processing, Post-Transcriptional
PubMed: 35063010
DOI: 10.1186/s13045-022-01224-4 -
Cell Research May 2018N-methyladenosine (mA), the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), has been shown to play critical roles in various normal... (Review)
Review
N-methyladenosine (mA), the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), has been shown to play critical roles in various normal bioprocesses such as tissue development, stem cell self-renewal and differentiation, heat shock or DNA damage response, and maternal-to-zygotic transition. The mA modification is deposited by the mA methyltransferase complex (MTC; i.e., writer) composed of METTL3, METTL14 and WTAP, and probably also VIRMA and RBM15, and can be removed by mA demethylases (i.e., erasers) such as FTO and ALKBH5. The fates of mA-modified mRNAs rely on the functions of distinct proteins that recognize them (i.e., readers), which may affect the stability, splicing, and/or translation of target mRNAs. Given the functional importance of the mA modification machinery in normal bioprocesses, it is not surprising that evidence is emerging that dysregulation of mA modification and the associated proteins also contributes to the initiation, progression, and drug response of cancers. In this review, we focus on recent advances in the study of biological functions and the underlying molecular mechanisms of dysregulated mA modification and the associated machinery in the pathogenesis and drug response of various types of cancers. In addition, we also discuss possible therapeutic interventions against the dysregulated mA machinery to treat cancers.
Topics: Adenosine; Carcinogenesis; Hematopoiesis; Humans; Neoplasms; RNA; Signal Transduction
PubMed: 29686311
DOI: 10.1038/s41422-018-0034-6 -
Nucleic Acids Research Jun 2018The methyltransferase like 3 (METTL3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for N6-methyladenosine (m6A)...
The methyltransferase like 3 (METTL3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for N6-methyladenosine (m6A) modification in diverse RNAs including mRNA, tRNA, rRNA, small nuclear RNA, microRNA precursor and long non-coding RNA. However, the characteristics of METTL3 in activation and post-translational modification (PTM) is seldom understood. Here we find that METTL3 is modified by SUMO1 mainly at lysine residues K177, K211, K212 and K215, which can be reduced by an SUMO1-specific protease SENP1. SUMOylation of METTL3 does not alter its stability, localization and interaction with METTL14 and WTAP, but significantly represses its m6A methytransferase activity resulting in the decrease of m6A levels in mRNAs. Consistently with this, the abundance of m6A in mRNAs is increased with re-expression of the mutant METTL3-4KR compared to that of wild-type METTL3 in human non-small cell lung carcinoma (NSCLC) cell line H1299-shMETTL3, in which endogenous METTL3 was knockdown. The alternation of m6A in mRNAs and subsequently change of gene expression profiles, which are mediated by SUMOylation of METTL3, may directly influence the soft-agar colony formation and xenografted tumor growth of H1299 cells. Our results uncover an important mechanism for SUMOylation of METTL3 regulating its m6A RNA methyltransferase activity.
Topics: Adenosine; Animals; Cell Cycle Proteins; HeLa Cells; Humans; Lysine; Methyltransferases; Mice, Nude; Nuclear Proteins; Protein Stability; RNA Splicing Factors; RNA, Messenger; Sumoylation; Transcriptome; Xenograft Model Antitumor Assays
PubMed: 29506078
DOI: 10.1093/nar/gky156 -
Science Translational Medicine Jun 2022Tumor evasion of immune destruction is associated with the production of immunosuppressive adenosine in the tumor microenvironment (TME). Anticancer therapies can...
Tumor evasion of immune destruction is associated with the production of immunosuppressive adenosine in the tumor microenvironment (TME). Anticancer therapies can trigger adenosine triphosphate (ATP) release from tumor cells, causing rapid formation of adenosine by the ectonucleotidases CD39 and CD73, thereafter exacerbating immunosuppression in the TME. The goal of this study was to develop an approach to facilitate cancer therapy-induced immunogenic cell death including ATP release and to limit ATP degradation into adenosine, in order to achieve durable antitumor immune response. Our approach was to construct reactive oxygen species (ROS)-producing nanoparticles that carry an ectonucleotidase inhibitor ARL67156 by electronic interaction and phenylboronic ester. Upon near-infrared irradiation, nanoparticle-produced ROS induced ATP release from MOC1 cancer cells in vitro and triggered the cleavage of phenylboronic ester, facilitating the release of ARL67156 from the nanoparticles. ARL67156 prevented conversion of ATP to adenosine and enhanced anticancer immunity in an MOC1-based coculture model. We tested this approach in mouse tumor models. Nanoparticle-based ROS-responsive drug delivery reprogramed the immunogenic landscape in tumors, eliciting tumor-specific T cell responses and tumor regression, conferring long-term survival in mouse models. We demonstrated that TME reprograming sets the stage for response to anti-programmed cell death protein 1 (PD1) immunotherapy, and the combination resulted in tumor regression in a 4T1 breast cancer mouse model that was resistant to PD1 blockade. Furthermore, our approach also induced immunological effects in patient-derived organotypic tumor spheroid model, suggesting potential translation of our nanoparticle approach for treating human cancers.
Topics: Adenosine; Adenosine Triphosphate; Animals; Cell Line, Tumor; Esters; Humans; Immunosuppression Therapy; Mice; Nanoparticles; Neoplasms; Reactive Oxygen Species; Tumor Microenvironment
PubMed: 35675434
DOI: 10.1126/scitranslmed.abh1261 -
Cell Research Jun 2018N-methyladenosine (mA) is a chemical modification present in multiple RNA species, being most abundant in mRNAs. Studies on enzymes or factors that catalyze, recognize,... (Review)
Review
N-methyladenosine (mA) is a chemical modification present in multiple RNA species, being most abundant in mRNAs. Studies on enzymes or factors that catalyze, recognize, and remove mA have revealed its comprehensive roles in almost every aspect of mRNA metabolism, as well as in a variety of physiological processes. This review describes the current understanding of the mA modification, particularly the functions of its writers, erasers, readers in RNA metabolism, with an emphasis on its role in regulating the isoform dosage of mRNAs.
Topics: Adenosine; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Humans; Methyltransferases; RNA; RNA Isoforms; RNA, Messenger; RNA-Binding Proteins; Transcriptome
PubMed: 29789545
DOI: 10.1038/s41422-018-0040-8