Base-resolution mapping reveals distinct m<sup>1</sup>A methylome in nuclear- and mitochondrial-encoded transcripts

Li, Xiaoyü; Xiong, Xushen; Zhang, Meiling; Wang, Kun; Chen, Ying; Zhou, Jun; Mao, Yuanhui; Lv, Jia; Yi, Danyang; Chen, Xiaowei; Wang, Chu; Qian, Shu‐Bing; Yi, Chengqi

doi:10.1101/202747

Cited by 49 publications

(139 citation statements)

References 55 publications

(43 reference statements)

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“…On the other hand, nuclear phosphoinositide stress signaling (Barlow, Laishram, & Anderson, ) during oxidative stress leads to Star‐PAP‐mediated regulation of cytoprotective enzymes HO‐1 (heme oxygenase‐1, Mellman et al, ) and NQO‐1 (NAD[P]H:Quinone Oxidoreductase; Gonzales, Mellman, & Anderson, ). Interestingly, Star‐PAP induces the use of APA of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene and this is essential for DNA damage‐induced increase of PTEN protein levels (W. Li, Li, et al, ; X. Li, Xiong, et al, ), indicating that Star‐PAP regulates APA in a signaling‐ and target gene‐specific manner. Genome/functional analysis of Star‐PAP and PIPKIα depleted cells indicated that mRNAs encoding anti‐invasive factors, such as CDH1, CDH13, FEZ1, KISS1R, NME1, WIF1, are also targets of this polyadenylation activity (Laishram & Anderson, ).…”

Section: Cleavage and Polyadenylationmentioning

confidence: 99%

“…The major mRNA modifications in the transcriptome of eukaryotic cells are N 6 ‐methyladenosine (m6A), N 6 , 2′‐O‐dimethyladenosine, 5‐methylcytidine, 5‐hydroxylmethylcytidine, inosine, pseudouridine, and N 1 ‐methyladenosine (Roundtree, Evans, Pan, & He, ). Most of our understanding in this relatively new field is based on developing technologies, so the cellular functions of each modification are in question (Boulias et al, ; Sendinc et al, ), and how many of these modifications found on mRNAs and ncRNAs are legitimate (Khoddami et al, ; W. Li, Li, et al, ; X. Li, Xiong, et al, ; Safra et al, ). However, m6A has been repeatedly demonstrated to be involved in post‐transcriptional regulation of gene expression (Yue et al, ; Yue, Liu, & He, ).…”

Section: Non‐polyadenylate 3′ End Modifications and Epitranscriptomicsmentioning

confidence: 99%

“…On the other hand, nuclear phosphoinositide stress signaling (Barlow, Laishram, & Anderson, 2010) during oxidative stress leads to Star-PAP-mediated regulation of cytoprotective enzymes HO-1 (heme oxygenase-1, Mellman et al, 2008) and NQO-1 (NAD[P]H:Quinone Oxidoreductase; . Interestingly, Star-PAP induces the use of APA of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene and this is essential for DNA damage-induced increase of PTEN protein levels (W. X. Li, Xiong, et al, 2017), indicating that Star-PAP regulates APA in a signaling-and target gene-specific manner.…”

Section: Poly(a) Polymerasesmentioning

confidence: 99%

“…Most of our understanding in this relatively new field is based on developing technologies, so the cellular functions of each modification are in question (Boulias et al, 2019;Sendinc et al, 2019), and how many of these modifications found on mRNAs and ncRNAs are legitimate (Khoddami et al, 2019;W. Li, Li, et al, 2017;X. Li, Xiong, et al, 2017;Safra et al, 2017).…”

Section: 0 End Processing and Epitranscriptomicsmentioning

confidence: 99%

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Connections between 3′ end processing and DNA damage response: Ten years later

Murphy

Kleiman

2019

WIREs RNA

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Ten years ago we reviewed how the cellular DNA damage response (DDR) is controlled by changes in the functional and structural properties of nuclear proteins, resulting in a timely coordinated control of gene expression that allows DNA repair. Expression of genes that play a role in DDR is regulated not only at transcriptional level during mRNA biosynthesis but also by changing steady‐state levels due to turnover of the transcripts. The 3′ end processing machinery, which is important in the regulation of mRNA stability, is involved in these gene‐specific responses to DNA damage. Here, we review the latest mechanistic connections described between 3′ end processing and DDR, with a special emphasis on alternative polyadenylation, microRNA and RNA binding proteins‐mediated deadenylation, and discuss the implications of deregulation of these steps in DDR and human disease. This article is categorized under: RNA Processing > 3′ End Processing RNA‐Based Catalysis > Miscellaneous RNA‐Catalyzed Reactions RNA in Disease and Development > RNA in Disease

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Section: Cleavage and Polyadenylationmentioning

confidence: 99%

Section: Non‐polyadenylate 3′ End Modifications and Epitranscriptomicsmentioning

confidence: 99%

Section: Poly(a) Polymerasesmentioning

confidence: 99%

Section: 0 End Processing and Epitranscriptomicsmentioning

confidence: 99%

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Connections between 3′ end processing and DNA damage response: Ten years later

Murphy

Kleiman

2019

WIREs RNA

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“…We next examined misincorporations at other mitochondrial mRNAs with annotated m 1 A sites. Studies by Safra et al 5 and Li et al 16 identified 11 and 5 putative mitochondrial m 1 A-containing protein-coding genes, respectively. Four mitochondrial mRNAs were common to both studies (MT-ND5, MT-CO1, MT-CO2 and MT-CO3).…”

Section: A-induced Misincorporations Are Not Readily Detected In mentioning

confidence: 99%

Antibody cross-reactivity accounts for widespread appearance of m¹A in 5’ UTRs

Grozhik

Olarerin-George

Sindelar

et al. 2019

Preprint

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N 1 -methyladenosine (m 1 A) was recently identified as a new mRNA modification based on its mapping to the 5' UTRs of thousands of mRNAs with an m 1 A-binding antibody. More recent studies have confirmed the prevalence of m 1 A, while others have questioned it. To address this discrepancy, we mapped m 1 A using ultra-deep RNA-Seq datasets based on m 1 A-induced misincorporations during reverse transcription. Using this approach, we find m 1 A only in the mitochondrial MT-ND5 transcript. In contrast, when we mapped m 1 A antibody-binding sites at single-nucleotide resolution, we found binding to transcription start nucleotides in mRNA 5' UTRs. Using different biochemical assays, we find that m 1 A is not present at these sites. Instead, we find that the m 1 A antibody exhibits m 1 A-independent binding to mRNA cap structures. We also tested a new and independently derived m 1 A antibody. We show that this m 1 A antibody lacks m 7 G cap-binding cross-reactivity, and notably does not map to 5' UTRs in the transcriptome. Our data demonstrate that high-stoichiometry m 1 A sites are rare in the transcriptome and that previous mapping of m 1 A to mRNA 5' UTRs are due to unintended binding of the m 1 A antibody to m 7 G cap structure in mRNA.Given the inconsistency in the different antibody-dependent m 1 A-mapping methods (Extended Data Fig. 1a-c), we sought to use an antibody-independent approach to detect m 1 A at singlenucleotide resolution in mRNA. For this approach, we took advantage of ultra-deep RNA-seq datasets and the fact that m 1 A is a "hard stop" modification, meaning it typically arrests cDNA synthesized by standard reverse transcriptases 7,8 (Extended Data Fig. 1d). However, SuperScript III will read through m 1 A at low frequency, resulting in misincorporations that are variable and sequence dependent 7,8 . Most m 1 A-induced misincorporations are A!T transitions that can be detected by sequencing the cDNA 7,8 . This approach can also detect other hard stop modifications, such as 3-methylcytidine (m 3 C), 3-methyluridine (m 3 U), N 2 ,N 2 -dimethylguanosine, and 1-methylguanosine, since these also produce misincorporations 7 . Therefore, the presence of misincorporated nucleotides can directly localize the m 1 A and other hard stop nucleotides in sequencing data 7,8 .

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RNA methylation in nuclear pre‐mRNA processing

2018

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Eukaryotic RNA can carry more than 100 different types of chemical modifications. Early studies have been focused on modifications of highly abundant RNA, such as ribosomal RNA and transfer RNA, but recent technical advances have made it possible to also study messenger RNA (mRNA). Subsequently, mRNA modifications, namely methylation, have emerged as key players in eukaryotic gene expression regulation. The most abundant and widely studied internal mRNA modification is N6‐methyladenosine (m6A), but the list of mRNA chemical modifications continues to grow as fast as interest in this field. Over the past decade, transcriptome‐wide studies combined with advanced biochemistry and the discovery of methylation writers, readers, and erasers revealed roles for mRNA methylation in the regulation of nearly every aspect of the mRNA life cycle and in diverse cellular, developmental, and disease processes. Although large parts of mRNA function are linked to its cytoplasmic stability and regulation of its translation, a number of studies have begun to provide evidence for methylation‐regulated nuclear processes. In this review, we summarize the recent advances in RNA methylation research and highlight how these new findings have contributed to our understanding of methylation‐dependent RNA processing in the nucleus.This article is categorized under: RNA Processing > RNA Editing and ModificationRNA Processing > Splicing Regulation/Alternative SplicingRNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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Base-resolution mapping reveals distinct m¹A methylome in nuclear- and mitochondrial-encoded transcripts

Cited by 49 publications

References 55 publications

Connections between 3′ end processing and DNA damage response: Ten years later

Connections between 3′ end processing and DNA damage response: Ten years later

Antibody cross-reactivity accounts for widespread appearance of m¹A in 5’ UTRs

RNA methylation in nuclear pre‐mRNA processing

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Base-resolution mapping reveals distinct m1A methylome in nuclear- and mitochondrial-encoded transcripts

Cited by 49 publications

References 55 publications

Connections between 3′ end processing and DNA damage response: Ten years later

Connections between 3′ end processing and DNA damage response: Ten years later

Antibody cross-reactivity accounts for widespread appearance of m1A in 5’ UTRs

RNA methylation in nuclear pre‐mRNA processing

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Product

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Base-resolution mapping reveals distinct m¹A methylome in nuclear- and mitochondrial-encoded transcripts

Antibody cross-reactivity accounts for widespread appearance of m¹A in 5’ UTRs