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

---

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

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

Опубликована: Май 31, 2021

Abstract Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since first tyrosine kinase inhibitor imatinib was approved enter market by US Food Drug Administration (FDA) 2001, an increasing number of small-molecule been developed for treatment malignancies. By December 2020, 89 antitumor FDA National Medical Products (NMPA) China. Despite great progress, anti-cancer still face many challenges, such as a low response rate drug resistance. To better promote development we conducted comprehensive review according target classification. We present all well important candidates clinical trials each target, discuss current provide insights perspectives research drugs.

Язык: Английский

---

Functions of N6-methyladenosine and its role in cancer

Molecular Cancer, Год журнала: 2019, Номер 18(1)

Опубликована: Дек. 1, 2019

N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A installed by methyltransferases, removed demethylases recognized reader proteins, regulate RNA metabolism including translation, splicing, export, degradation microRNA processing. Alteration levels participates cancer pathogenesis development via expression tumor-related genes like BRD4, MYC, SOCS2 EGFR. In this review, we elaborate recent advances research enzymes. We also highlight underlying mechanism progression. Finally, review corresponding potential targets therapy.

Язык: Английский

---

Alternative Splicing Regulatory Networks: Functions, Mechanisms, and Evolution

Molecular Cell, Год журнала: 2019, Номер 76(2), С. 329 - 345

Опубликована: Окт. 1, 2019

Язык: Английский

---

A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA

Cell, Год журнала: 2020, Номер 181(7), С. 1582 - 1595.e18

Опубликована: Июнь 1, 2020

N6-methyladenosine (m6A) is the most abundant mRNA nucleotide modification and regulates critical aspects of cellular physiology differentiation. m6A thought to mediate its effects through a complex network interactions between different sites three functionally distinct cytoplasmic YTHDF m6A-binding proteins (DF1, DF2, DF3). In contrast prevailing model, we show that DF bind same m6A-modified mRNAs rather than mRNAs. Furthermore, find do not induce translation in HeLa cells. Instead, paralogs act redundantly degradation The ability regulate stability differentiation becomes evident only when all are depleted simultaneously. Our study reveals unified model function which subjected combined action proportion number sites.

Язык: Английский

---

ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment

Proceedings of the National Academy of Sciences, Год журнала: 2020, Номер 117(33), С. 20159 - 20170

Опубликована: Авг. 3, 2020

Significance N 6 -methylation of adenosine (m A) RNA modification plays important roles in development and tumorigenesis. The functions mechanisms m A demethylases during cancer immunotherapy is still unclear. Here we employed melanoma colon syngeneic mouse models to study the ALKBH5 FTO anti–PD-1 antibody GVAX vaccination therapy. We found that knockout tumor cells enhances efficacy prolonged survival. modulates target gene expression splicing, leading changes metabolite contents, such as lactate microenvironment, which regulates suppressive lymphocytes Treg myeloid-derived suppressor cell accumulations. Importantly, by using ALKBH5-specific inhibitor, observed similar phenotype, indicating future translational application our findings.

Язык: Английский

---

The emerging role of RNA modifications in the regulation of mRNA stability

Experimental & Molecular Medicine, Год журнала: 2020, Номер 52(3), С. 400 - 408

Опубликована: Март 1, 2020

Many studies have highlighted the importance of tight regulation mRNA stability in control gene expression. largely depends on nucleotide sequence, which affects secondary and tertiary structures mRNAs, accessibility various RNA-binding proteins to mRNAs. Recent advances high-throughput RNA-sequencing techniques resulted elucidation important roles played by modifications sequences regulating stability. To date, hundreds different RNA been characterized. Among them, several modifications, including N

Язык: Английский

---

The evolving metabolic landscape of chromatin biology and epigenetics

Nature Reviews Genetics, Год журнала: 2020, Номер 21(12), С. 737 - 753

Опубликована: Сен. 9, 2020

Язык: Английский

---

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

---

Stem cell programs in cancer initiation, progression, and therapy resistance

Theranostics, Год журнала: 2020, Номер 10(19), С. 8721 - 8743

Опубликована: Янв. 1, 2020

Over the past few decades, substantial evidence has convincingly revealed existence of cancer stem cells (CSCs) as a minor subpopulation in cancers, contributing to an aberrantly high degree cellular heterogeneity within tumor. CSCs are functionally defined by their abilities self-renewal and differentiation, often response cues from microenvironment. Biological phenotypes regulated integrated transcriptional, post-transcriptional, metabolic, epigenetic regulatory networks. contribute tumor progression, therapeutic resistance, disease recurrence through sustained proliferation, invasion into normal tissue, promotion angiogenesis, evasion immune system, resistance conventional anticancer therapies. Therefore, elucidation molecular mechanisms that drive cell maintenance, plasticity, will enhance our ability improve effectiveness targeted therapies for CSCs. In this review, we highlight key features regulate CSC function initiation, therapy resistance. We discuss factors such quiescence, induction epithelial-to-mesenchymal transition (EMT), DNA damage-induced death. evaluate approaches eliminating therapy-resistant subpopulations, including drugs target signaling pathways surface markers, viral therapies, awakening quiescent CSCs, immunotherapy. also assess impact new technologies, single-cell sequencing CRISPR-Cas9 screening, on investigation biological properties Moreover, challenges remain be addressed coming years, experimental investigating obstacles targeting

Язык: Английский

---