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Molecular Cell May 2022Tumor-infiltrating myeloid cells (TIMs) are crucial cell populations involved in tumor immune escape, and their functions are regulated by multiple epigenetic...
Tumor-infiltrating myeloid cells (TIMs) are crucial cell populations involved in tumor immune escape, and their functions are regulated by multiple epigenetic mechanisms. The precise regulation mode of RNA N-methyladenosine (mA) modification in controlling TIM function is still poorly understood. Our study revealed that the increased expression of methyltransferase-like 3 (METTL3) in TIMs was correlated with the poor prognosis of colon cancer patients, and myeloid deficiency of METTL3 attenuated tumor growth in mice. METTL3 mediated mA modification on Jak1 mRNA in TIMs, the mA-YTHDF1 axis enhanced JAK1 protein translation efficiency and subsequent phosphorylation of STAT3. Lactate accumulated in tumor microenvironment potently induced METTL3 upregulation in TIMs via H3K18 lactylation. Interestingly, we identified two lactylation modification sites in the zinc-finger domain of METTL3, which was essential for METTL3 to capture target RNA. Our results emphasize the importance of lactylation-driven METTL3-mediated RNA mA modification for promoting the immunosuppressive capacity of TIMs.
Topics: Adenosine; Animals; Humans; Immunosuppression Therapy; Methyltransferases; Mice; Myeloid Cells; Neoplasms; RNA; Tumor Microenvironment
PubMed: 35320754
DOI: 10.1016/j.molcel.2022.02.033 -
Nucleic Acids Research Jul 2021Gene expression is regulated at many levels including co- or post-transcriptionally, where chemical modifications are added to RNA on riboses and bases. Expression... (Review)
Review
Gene expression is regulated at many levels including co- or post-transcriptionally, where chemical modifications are added to RNA on riboses and bases. Expression control via RNA modifications has been termed 'epitranscriptomics' to keep with the related 'epigenomics' for DNA modification. One such RNA modification is the N6-methylation found on adenosine (m6A) and 2'-O-methyladenosine (m6Am) in most types of RNA. The N6-methylation can affect the fold, stability, degradation and cellular interaction(s) of the modified RNA, implicating it in processes such as splicing, translation, export and decay. The multiple roles played by this modification explains why m6A misregulation is connected to multiple human cancers. The m6A/m6Am writer enzymes are RNA methyltransferases (MTases). Structures are available for functionally characterized m6A RNA MTases from human (m6A mRNA, m6A snRNA, m6A rRNA and m6Am mRNA MTases), zebrafish (m6Am mRNA MTase) and bacteria (m6A rRNA MTase). For each of these MTases, we describe their overall domain organization, the active site architecture and the substrate binding. We identify areas that remain to be investigated, propose yet unexplored routes for structural characterization of MTase:substrate complexes, and highlight common structural elements that should be described for future m6A/m6Am RNA MTase structures.
Topics: Adenosine; Animals; Bacteria; Humans; Methyltransferases; Zebrafish Proteins
PubMed: 34023900
DOI: 10.1093/nar/gkab378 -
Journal of Hematology & Oncology Aug 2020N-methyladenosine (mA) is the most abundant mRNA modification and is catalyzed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole... (Review)
Review
N-methyladenosine (mA) is the most abundant mRNA modification and is catalyzed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. Accumulating evidence in recent years reveals that METTL3 plays key roles in a variety of cancer types, either dependent or independent on its mA RNA methyltransferase activity. While the roles of mA modifications in cancer have been extensively reviewed elsewhere, the critical functions of METTL3 in various types of cancer, as well as the potential targeting of METTL3 as cancer treatment, have not yet been highlighted. Here we summarize our current understanding both on the oncogenic and tumor-suppressive functions of METTL3, as well as the underlying molecular mechanisms. The well-documented protein structure of the METTL3/METTL14 heterodimer provides the basis for potential therapeutic targeting, which is also discussed in this review.
Topics: Adenosine; Antineoplastic Agents; Binding, Competitive; Carcinogens; Drug Design; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Humans; Methylation; Methyltransferases; Models, Molecular; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Oncogenes; Protein Conformation; Protein Domains; RNA Processing, Post-Transcriptional; RNA, Neoplasm; Recombinant Fusion Proteins; Substrate Specificity; Tumor Suppressor Proteins
PubMed: 32854717
DOI: 10.1186/s13045-020-00951-w -
Wiley Interdisciplinary Reviews. RNA Mar 2022The N6-methyladenosine (m6A) RNA methyltransferase METTL16 is an emerging player in the RNA modification landscape of the human cell. Originally thought to be a... (Review)
Review
The N6-methyladenosine (m6A) RNA methyltransferase METTL16 is an emerging player in the RNA modification landscape of the human cell. Originally thought to be a ribosomal RNA methyltransferase, it has now been shown to bind and methylate the MAT2A messenger RNA (mRNA) and U6 small nuclear RNA (snRNA). It has also been shown to bind the MALAT1 long noncoding RNA and several other RNAs. METTL16's methyltransferase domain contains the Rossmann-like fold of class I methyltransferases and uses S-adenosylmethionine (SAM) as the methyl donor. It has an RNA methylation consensus sequence of UACAGARAA (modified A underlined), and structural requirements for its known RNA interactors. In addition to the methyltransferase domain, METTL16 protein has two other RNA binding domains, one of which resides in a vertebrate conserved region, and a putative nuclear localization signal. The role of METTL16 in the cell is still being explored, however evidence suggests it is essential for most cells. This is currently hypothesized to be due to its role in regulating the splicing of MAT2A mRNA in response to cellular SAM levels. However, one of the more pressing questions remaining is what role METTL16's methylation of U6 snRNA plays in splicing and potentially cellular survival. METTL16 also has several other putative coding and noncoding RNA interactors but the definitive methylation status of those RNAs and the role METTL16 plays in their life cycle is yet to be determined. Overall, METTL16 is an intriguing RNA binding protein and methyltransferase whose important functions in the cell are just beginning to be understood. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.
Topics: Humans; Methionine Adenosyltransferase; Methylation; Methyltransferases; RNA, Long Noncoding; RNA, Messenger; S-Adenosylmethionine
PubMed: 34227247
DOI: 10.1002/wrna.1681 -
Cells Jul 20205-methylcytosine is often associated as an epigenetic modifier in DNA. However, it is also found increasingly in a plethora of RNA species, predominantly transfer RNAs,... (Review)
Review
5-methylcytosine is often associated as an epigenetic modifier in DNA. However, it is also found increasingly in a plethora of RNA species, predominantly transfer RNAs, but increasingly found in cytoplasmic and mitochondrial ribosomal RNAs, enhancer RNAs, and a number of long noncoding RNAs. Moreover, this modification can also be found in messenger RNAs and has led to an increasing appreciation that RNA methylation can functionally regulate gene expression and cellular activities. In mammalian cells, the addition of m5C to RNA cytosines is carried out by enzymes of the NOL1/NOP2/SUN domain (NSUN) family as well as the DNA methyltransferase homologue DNMT2. In this regard, NSUN2 is a critical RNA methyltransferase for adding m5C to mRNA. In this review, using non-small cell lung cancer and other cancers as primary examples, we discuss the recent developments in the known functions of this RNA methyltransferase and its potential critical role in cancer.
Topics: 5-Methylcytosine; Animals; Breast Neoplasms; Colorectal Neoplasms; Female; Humans; Lung Neoplasms; Methylation; Methyltransferases; Mice; Phylogeny; RNA, Messenger
PubMed: 32708015
DOI: 10.3390/cells9081758 -
Cells Mar 2022Cardiometabolic diseases (CMDs) are currently the leading cause of death and disability worldwide, and their underlying regulatory mechanisms remain largely unknown.... (Review)
Review
Cardiometabolic diseases (CMDs) are currently the leading cause of death and disability worldwide, and their underlying regulatory mechanisms remain largely unknown. N6-methyladenosine (m6A) methylation, the most common and abundant epigenetic modification of eukaryotic mRNA, is regulated by m6A methyltransferase, demethylase, and the m6A binding protein, which affect the transcription, cleavage, translation, and degradation of target mRNA. m6A methylation plays a vital role in the physiological and pathological processes of CMDs. In this review, we summarize the role played by m6A methylation in CMDs, including obesity, hypertension, pulmonary hypertension, ischemic heart disease, myocardial hypertrophy, heart failure, and atherosclerosis. We also describe mechanisms that potentially involve the participation of m6A methylation, such as those driving calcium homeostasis, circadian rhythm, lipid metabolism, autophagy, macrophage response, and inflammation. m6A methylation and its regulators are expected to be targets for the treatment of CMDs.
Topics: Adenosine; Cardiovascular Diseases; Humans; Methylation; Methyltransferases; RNA, Messenger
PubMed: 35406663
DOI: 10.3390/cells11071101 -
Journal of Translational Medicine May 2022In recent years, 5-methylcytosine (mC) RNA modification has emerged as a key player in regulating RNA metabolism and function through coding as well as non-coding RNAs.... (Review)
Review
In recent years, 5-methylcytosine (mC) RNA modification has emerged as a key player in regulating RNA metabolism and function through coding as well as non-coding RNAs. Accumulating evidence has shown that mC modulates the stability, translation, transcription, nuclear export, and cleavage of RNAs to mediate cell proliferation, differentiation, apoptosis, stress responses, and other biological functions. In humans, mC RNA modification is catalyzed by the NOL1/NOP2/sun (NSUN) family and DNA methyltransferase 2 (DNMT2). These RNA modifiers regulate the expression of multiple oncogenes such as fizzy-related-1, forkhead box protein C2, Grb associated-binding protein 2, and TEA domain transcription factor 1, facilitating the pathogenesis and progression of cancers. Furthermore, the aberrant expression of methyltransferases have been identified in various cancers and used to predict the prognosis of patients. In this review, we present a comprehensive overview of mC RNA methyltransferases. We specifically highlight the potential mechanism of action of mC in cancer. Finally, we discuss the prospect of mC-relative studies.
Topics: 5-Methylcytosine; Humans; Methyltransferases; Neoplasms; RNA; RNA Processing, Post-Transcriptional
PubMed: 35562754
DOI: 10.1186/s12967-022-03427-2 -
Stem Cell Reviews and Reports Jan 2023The methyltransferase-like (METTL) family is a diverse group of methyltransferases that can methylate nucleotides, proteins, and small molecules. Despite this diverse... (Review)
Review
The methyltransferase-like (METTL) family is a diverse group of methyltransferases that can methylate nucleotides, proteins, and small molecules. Despite this diverse array of substrates, they all share a characteristic seven-beta-strand catalytic domain, and recent evidence suggests many also share an important role in stem cell biology. The most well characterized family members METTL3 and METTL14 dimerize to form an N-methyladenosine (mA) RNA methyltransferase with established roles in cancer progression. However, new mouse models indicate that METTL3/METTL14 are also important for embryonic stem cell (ESC) development and postnatal hematopoietic and neural stem cell self-renewal and differentiation. METTL1, METTL5, METTL6, METTL8, and METTL17 also have recently identified roles in ESC pluripotency and differentiation, while METTL11A/11B, METTL4, METTL7A, and METTL22 have been shown to play roles in neural, mesenchymal, bone, and hematopoietic stem cell development, respectively. Additionally, a variety of other METTL family members are translational regulators, a role that could place them as important players in the transition from stem cell quiescence to differentiation. Here we will summarize what is known about the role of METTL proteins in stem cell differentiation and highlight the connection between their growing importance in development and their established roles in oncogenesis.
Topics: Mice; Animals; Methyltransferases; RNA; Embryonic Stem Cells; Cell Differentiation; Biology; Neoplasms
PubMed: 36094754
DOI: 10.1007/s12015-022-10444-7 -
Journal of Hematology & Oncology Feb 2022RNA modification plays a crucial role in many biological functions, and its abnormal regulation is associated with the progression of cancer. Among them, N-methyladenine... (Review)
Review
RNA modification plays a crucial role in many biological functions, and its abnormal regulation is associated with the progression of cancer. Among them, N-methyladenine (mA) is the most abundant RNA modification. Methyltransferase-like 14 (METTL14) is the central component of the mA methylated transferase complex, which is involved in the dynamic reversible process of mA modification. METTL14 acts as both an oncogene and tumor suppressor gene to regulate the occurrence and development of various cancers. The abnormal mA level induced by METTL14 is related to tumorigenesis, proliferation, metastasis, and invasion. To date, the molecular mechanism of METTL14 in various malignant tumors has not been fully studied. In this paper, we systematically summarize the latest research progress on METTL14 as a new biomarker for cancer diagnosis and its biological function in human tumors and discuss its potential clinical application. This study aims to provide new ideas for targeted therapy and improved prognoses in cancer.
Topics: Adenine; Animals; Carcinogenesis; Gene Expression Regulation, Neoplastic; Humans; Methylation; Methyltransferases; Neoplasms; Prognosis; RNA
PubMed: 35115038
DOI: 10.1186/s13045-022-01231-5 -
Cell May 2017Maintenance of proper levels of the methyl donor S-adenosylmethionine (SAM) is critical for a wide variety of biological processes. We demonstrate that the N-adenosine...
Maintenance of proper levels of the methyl donor S-adenosylmethionine (SAM) is critical for a wide variety of biological processes. We demonstrate that the N-adenosine methyltransferase METTL16 regulates expression of human MAT2A, which encodes the SAM synthetase expressed in most cells. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhanced splicing of a retained intron. Induction requires METTL16 and its methylation substrate, a vertebrate conserved hairpin (hp1) in the MAT2A 3' UTR. Increasing METTL16 occupancy on the MAT2A 3' UTR is sufficient to induce efficient splicing. We propose that, under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which promotes MAT2A splicing. We further show that METTL16 is the long-unknown methyltransferase for the U6 spliceosomal small nuclear RNA (snRNA). These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.
Topics: Animals; Base Sequence; Gene Expression Regulation, Enzymologic; HEK293 Cells; Humans; Introns; Inverted Repeat Sequences; Methionine Adenosyltransferase; Methylation; Methyltransferases; RNA Splicing; S-Adenosylmethionine; Schizosaccharomyces
PubMed: 28525753
DOI: 10.1016/j.cell.2017.05.003