The role of m6A modification in the biological functions and diseases

Signal Transduction and Targeted Therapy, Год журнала: 2021, Номер 6(1)

Опубликована: Фев. 21, 2021

Abstract N 6 -methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher cells. m6A modified by methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, KIAA1429, and, removed demethylases, erasers, including FTO ALKBH5. It recognized m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 HNRNPA2B1, also known “readers”. Recent studies have shown that RNA plays essential role both physiological pathological conditions, initiation progression of different types human cancers. In this review, we discuss how methylation influences progressions hematopoietic, central nervous reproductive systems. We will mainly focus on recent progress identifying biological functions underlying molecular mechanisms methylation, its regulators downstream target genes, during cancer above propose process offer potential targets for therapy future.

Язык: Английский

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Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion

Cancer Cell, Год журнала: 2020, Номер 38(1), С. 79 - 96.e11

Опубликована: Июнь 11, 2020

Язык: Английский

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Roles of METTL3 in cancer: mechanisms and therapeutic targeting

Journal of Hematology & Oncology, Год журнала: 2020, Номер 13(1)

Опубликована: Авг. 27, 2020

N6-methyladenosine (m6A) is the most abundant mRNA modification and catalyzed by methyltransferase complex, in which methyltransferase-like 3 (METTL3) sole catalytic subunit. Accumulating evidence recent years reveals that METTL3 plays key roles a variety of cancer types, either dependent or independent on its m6A RNA activity. While modifications have been extensively reviewed elsewhere, critical functions various types cancer, as well potential targeting treatment, not yet highlighted. Here we summarize our current understanding both oncogenic tumor-suppressive METTL3, underlying molecular mechanisms. The well-documented protein structure METTL3/METTL14 heterodimer provides basis for therapeutic targeting, also discussed this review.

Язык: Английский

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A comprehensive review of m6A/m6Am RNA methyltransferase structures

Nucleic Acids Research, Год журнала: 2021, Номер 49(13), С. 7239 - 7255

Опубликована: Апрель 26, 2021

Abstract 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 has been termed ‘epitranscriptomics’ keep with the related ‘epigenomics’ for DNA modification. One such modification N6-methylation found adenosine (m6A) 2′-O-methyladenosine (m6Am) in most types of RNA. The can affect fold, stability, degradation cellular interaction(s) modified RNA, implicating it processes as splicing, translation, export decay. multiple roles played by this explains why m6A misregulation connected human cancers. m6A/m6Am writer enzymes methyltransferases (MTases). Structures available functionally characterized MTases from (m6A mRNA, snRNA, rRNA m6Am mRNA MTases), zebrafish (m6Am MTase) bacteria MTase). For each these MTases, we describe their overall domain organization, active site architecture substrate binding. We identify areas that remain be investigated, propose yet unexplored routes structural characterization MTase:substrate complexes, highlight common elements should described future MTase structures.

Язык: Английский

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RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia

Cell stem cell, Год журнала: 2020, Номер 27(1), С. 64 - 80.e9

Опубликована: Май 12, 2020

Язык: Английский

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R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis

Molecular Cell, Год журнала: 2021, Номер 81(5), С. 922 - 939.e9

Опубликована: Янв. 14, 2021

Язык: Английский

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Role of m6A RNA methylation in cardiovascular disease (Review)

International Journal of Molecular Medicine, Год журнала: 2020, Номер 46(6), С. 1958 - 1972

Опубликована: Окт. 6, 2020

N6‑methyladenosine (m6A) is the most prevalent and abundant type of internal post‑transcriptional RNA modification in eukaryotic cells. Multiple types RNA, including mRNAs, rRNAs, tRNAs, long non‑coding RNAs microRNAs, are involved m6A methylation. The biological function dynamically reversibly mediated by methyltransferases (writers), demethylases (erasers) binding proteins (readers). methyltransferase complex responsible for catalyzation typically made up methyltransferase‑like (METTL)3, METTL14 Wilms tumor 1‑associated protein. Erasers remove methylation fat mass obesity‑associated protein ALKB homolog 5. Readers play a role through recognition m6A‑modified targeted RNA. YT521‑B homology domain family, heterogeneous nuclear ribonucleoprotein insulin‑like growth factor 2 mRNA‑binding serve as readers. on transcripts plays pivotal regulation downstream molecular events functions, such splicing, transport, stability translatability at level. dysregulation associated with cancer, drug resistance, virus replication pluripotency embryonic stem Recently, number studies have identified aberrant cardiovascular diseases (CVDs), cardiac hypertrophy, heart failure, arterial aneurysm, vascular calcification pulmonary hypertension. aim present review article was to summarize recent research progress CVD give brief perspective its prospective applications CVD.

Язык: Английский

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METTL16 exerts an m6A-independent function to facilitate translation and tumorigenesis

Nature Cell Biology, Год журнала: 2022, Номер 24(2), С. 205 - 216

Опубликована: Фев. 1, 2022

Язык: Английский

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Mechanism of RNA modification N6-methyladenosine in human cancer

Molecular Cancer, Год журнала: 2020, Номер 19(1)

Опубликована: Июнь 8, 2020

Abstract Since the breakthrough discoveries of DNA and histone modifications, field RNA modifications has gained increasing interest in scientific community. The discovery N6-methyladenosine (m6A), a predominantly internal epigenetic modification eukaryotes mRNA, heralded creation epi-transcriptomics. This post-transcriptional is dynamic reversible, regulated by methylases, demethylases proteins that preferentially recognize m6A modifications. Altered levels affect processing, degradation translation, thereby disrupting gene expression key cellular processes, ultimately resulting tumor initiation progression. Furthermore, inhibitors regulators m6A-related factors have been explored as therapeutic approaches for treating cancer. In present review, mechanisms modification, clinicopathological relevance alterations, type frequency alterations multiple functions it regulates different types cancer are discussed.

Язык: Английский

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ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1

Molecular Cancer, Год журнала: 2020, Номер 19(1)

Опубликована: Авг. 10, 2020

Abstract Background N6-methyladenosine (m 6 A) modification is an emerging layer of epigenetic regulation which widely implicated in the tumorigenicity hepatocellular carcinoma (HCC), offering a novel perspective for investigating molecular pathogenesis this disease. The role AlkB homolog 5 (ALKBH5), one m A demethylases, has not been fully explored HCC. Here we clarify biological profile and potential mechanisms ALKBH5 Methods Expression its correlation with clinicopathological characteristics HCC were evaluated using tissue microarrays online datasets. And effects determined vitro vivo. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined (RNA-seq), following dot blot, MeRIP-qPCR, RIP-qPCR or dual luciferase reporter assays employed to screen validate candidate targets ALKBH5. Results We demonstrated that was down-regulated HCC, decreased expression independent prognostic factor worse survival patients. Functionally, suppressed proliferation invasion capabilities cells Mechanistically, ALKBH5-mediated demethylation led post-transcriptional inhibition LY6/PLAUR Domain Containing 1 (LYPD1), could be recognized stabilized by effector IGF2BP1. In addition, identified LYPD1 induced oncogenic behaviors tumors contrast Dysregulation ALKBH5/LYPD1 axis impelled progression Conclusion Our study reveals ALKBH5, characterized as tumor suppressor, attenuates via A-dependent manner cells. findings enrich landscape A-modulated malignancy, provide new insights into biomarkers therapeutic treatment.

Язык: Английский

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