The RNA modification landscape in human disease DOI Open Access

Nicky Jonkhout,

Julia Tran,

Martin A. Smith

et al.

RNA, Journal Year: 2017, Volume and Issue: 23(12), P. 1754 - 1769

Published: Aug. 30, 2017

RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent result systematic efforts map quantify various transcriptome-wide manner, revealing that are reversible, dynamically regulated, far more widespread than originally thought, involved major biological processes, including cell differentiation, sex determination, stress responses. Here we summarize the state knowledge provide catalog their links neurological disorders, cancers, other diseases. With advent direct RNA-sequencing technologies, expect this will help prioritize those for maps.

Language: Английский

5-methylcytosine promotes mRNA export — NSUN2 as the methyltransferase and ALYREF as an m5C reader DOI Creative Commons
Xin Yang, Ying Yang, Baofa Sun

et al.

Cell Research, Journal Year: 2017, Volume and Issue: 27(5), P. 606 - 625

Published: April 18, 2017

5-methylcytosine (m5C) is a post-transcriptional RNA modification identified in both stable and highly abundant tRNAs rRNAs, mRNAs. However, its regulatory role mRNA metabolism still largely unknown. Here, we reveal that m5C modification enriched CG-rich regions immediately downstream of translation initiation sites has conserved, tissue-specific dynamic features across mammalian transcriptomes. Moreover, formation mRNAs mainly catalyzed by the methyltransferase NSUN2, specifically recognized export adaptor ALYREF as shown vitro vivo studies. NSUN2 modulates ALYREF's nuclear-cytoplasmic shuttling, RNA-binding affinity associated export. Dysregulation ALYREF-mediated upon depletion could be restored reconstitution wild-type but not methyltransferase-defective NSUN2. Our study provides comprehensive profiles transcriptomes suggests an essential for regulation.

Language: Английский

Citations

841
RNA in cancer DOI
Gregory J. Goodall, Vihandha O. Wickramasinghe

Nature reviews. Cancer, Journal Year: 2020, Volume and Issue: 21(1), P. 22 - 36

Published: Oct. 20, 2020

Language: Английский

Citations

837
VIRMA mediates preferential m6A mRNA methylation in 3′UTR and near stop codon and associates with alternative polyadenylation DOI Creative Commons
Yanan Yue, Jun Liu, Xiaolong Cui

et al.

Cell Discovery, Journal Year: 2018, Volume and Issue: 4(1)

Published: Feb. 23, 2018

N6-methyladenosine (m6A) is enriched in 3'untranslated region (3'UTR) and near stop codon of mature polyadenylated mRNAs mammalian systems has regulatory roles eukaryotic mRNA transcriptome switch. Significantly, the mechanism for this modification preference remains unknown, however. Herein we report a characterization full m6A methyltransferase complex HeLa cells identifying METTL3/METTL14/WTAP/VIRMA/HAKAI/ZC3H13 as key components, show that VIRMA mediates preferential methylation 3'UTR codon. Biochemical studies reveal recruits catalytic core components METTL3/METTL14/WTAP to guide region-selective methylations. Around 60% immunoprecipitation targets manifest strong enrichment 3'UTR. Depletions METTL3 induce lengthening several hundred with over 50% common. associates polyadenylation cleavage factors CPSF5 CPSF6 an RNA-dependent manner. Depletion leads significant shortening 2800 mRNAs, 84% which are modified have increased peak density after knockdown. Together, our provide insights into deposition specificity its correlation alternative polyadenylation.

Language: Английский

Citations

807
m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer DOI Creative Commons
Bo Zhang, Qiong Wu, Ben Li

et al.

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: March 12, 2020

The epigenetic regulation of immune response has been demonstrated in recent studies. Nonetheless, potential roles RNA N6-methyladenosine (m6A) modification tumor microenvironment (TME) cell infiltration remain unknown.We comprehensively evaluated the m6A patterns 1938 gastric cancer samples based on 21 regulators, and systematically correlated these with TME cell-infiltrating characteristics. m6Ascore was constructed to quantify individual tumors using principal component analysis algorithms.Three distinct were determined. characteristics under three highly consistent phenotypes including immune-excluded, immune-inflamed immune-desert phenotypes. We evaluation within could predict stages inflammation, subtypes, stromal activity, genetic variation, patient prognosis. Low m6Ascore, characterized by increased mutation burden activation immunity, indicated an inflamed phenotype, 69.4% 5-year survival. Activation stroma lack effective observed high subtype, indicating a non-inflamed immune-exclusion poorer also linked neoantigen load enhanced anti-PD-1/L1 immunotherapy. Two immunotherapy cohorts confirmed patients lower significant therapeutic advantages clinical benefits.This work revealed played nonnegligible role formation diversity complexity. Evaluating pattern will contribute enhancing our cognition characterization guiding more strategies.

Language: Английский

Citations

788
Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them DOI
Kathrin Leppek, Rhiju Das, Maria Barna

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2017, Volume and Issue: 19(3), P. 158 - 174

Published: Nov. 22, 2017

Language: Английский

Citations

755
The role of m6A RNA methylation in cancer DOI Creative Commons
Ting Sun, Ruiyan Wu, Liang Ming

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2019, Volume and Issue: 112, P. 108613 - 108613

Published: Feb. 19, 2019

N6-methyladenosine (m6A), the most abundant internal modification of RNA in eukaryotic cells, has gained increasing attention recent years. The m6A affects multiple aspects metabolism, ranging from processing, nuclear export, translation to decay. Emerging evidence suggests that methylation plays a critical role cancer through various mechanisms. Moreover, provided more possibilities for early diagnosis and treatment cancers. In this review, we focus on m6A-associated mechanisms functions several major malignancies summarize dual as well its prospects cancer.

Language: Английский

Citations

744
m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer DOI
Jun Liu, Mark A. Eckert, Bryan T. Harada

et al.

Nature Cell Biology, Journal Year: 2018, Volume and Issue: 20(9), P. 1074 - 1083

Published: Aug. 17, 2018

Language: Английский

Citations

662
RNA N6-methyladenosine modification in cancers: current status and perspectives DOI Creative Commons
Xiaolan Deng, Rui Su, Hengyou Weng

et al.

Cell Research, Journal Year: 2018, Volume and Issue: 28(5), P. 507 - 517

Published: April 23, 2018

N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), has been shown to play critical roles various normal bioprocesses such as tissue development, stem cell self-renewal and differentiation, heat shock or DNA damage response, maternal-to-zygotic transition. The m6A is deposited by methyltransferase complex (MTC; i.e., writer) composed of METTL3, METTL14 WTAP, probably also VIRMA RBM15, can be removed demethylases (i.e., erasers) FTO ALKBH5. fates m6A-modified mRNAs rely on functions distinct proteins that recognize them readers), which may affect stability, splicing, and/or translation target mRNAs. Given functional importance machinery bioprocesses, it not surprising evidence emerging dysregulation associated contributes initiation, progression, drug response cancers. In this review, we focus recent advances study biological underlying molecular mechanisms dysregulated pathogenesis types addition, discuss possible therapeutic interventions against treat

Language: Английский

Citations

660
Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation DOI Creative Commons
Ki‐Jun Yoon, Francisca Rojas,

Caroline Vissers

et al.

Cell, Journal Year: 2017, Volume and Issue: 171(4), P. 877 - 889.e17

Published: Sept. 29, 2017

Language: Английский

Citations

651
METTL3-mediated m6A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance DOI
Qiang Wang, Chen Chen, Qingqing Ding

et al.

Gut, Journal Year: 2019, Volume and Issue: 69(7), P. 1193 - 1205

Published: Oct. 3, 2019

Objective N 6 -methyladenosine (m A) RNA methylation and its associated methyltransferase METTL3 are involved in tumour initiation progression via the regulation of function. This study explored biological function clinical significance gastric cancer (GC). Design The prognostic value expression was evaluated using tissue microarray immunohistochemical staining analyses a human GC cohort. role mechanism growth liver metastasis were determined vitro vivo. Results level m A significantly increased GC, main regulator abundant modification. elevated tissues with poor prognosis. Multivariate Cox regression analysis revealed that an independent factor effective predictor patients GC. Moreover, overexpression promoted proliferation Mechanistically, P300-mediated H3K27 acetylation activation promoter induced transcription, which stimulated modification HDGF mRNA, reader IGF2BP3 then directly recognised bound to site on mRNA enhanced stability. Secreted angiogenesis, while nuclear activated GLUT4 ENO2 expression, followed by increase glycolysis cells, correlated subsequent metastasis. Conclusions Elevated promotes angiogenesis indicating is potential biomarker therapeutic target for

Language: Английский

Citations

636