NML-mediated rRNA base methylation links ribosomal subunit formation to cell proliferation in a p53-dependent manner

Waku, Tsuyoshi; Nakajima, Yuka; Yokoyama, Wataru; Nomura, Naoto; Kako, Koichiro; Kobayashi, Akira; Shimizu, Toshiyuki; Fukamizu, Akiyoshi

doi:10.1242/jcs.183723

Cited by 85 publications

(62 citation statements)

References 58 publications

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“…NML introduces specific m 1 A 28S ribosomal RNA methylation in human and mouse cells and contributes to 60S subunit formation. Depletion of NML activates the p53 pathway and thereby regulates cellular proliferation ( 90 ). Interestingly, NML is important for the induction of drug-induced senescence in tumor cells.…”

Section: Upcoming Innovative Therapeutic Approachesmentioning

confidence: 99%

The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy

2017

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Cellular senescence describes an irreversible growth arrest characterized by distinct morphology, gene expression pattern, and secretory phenotype. The final or intermediate stages of senescence can be reached by different genetic mechanisms and in answer to different external and internal stresses. It has been maintained in the literature but never proven by clearcut experiments that the induction of senescence serves the evolutionary purpose of protecting the individual from development and growth of cancers. This hypothesis was recently scrutinized by new experiments and found to be partly true, but part of the gene activities now known to happen in senescence are also needed for cancer growth, leading to the view that senescence is a double-edged sword in cancer development. In current cancer therapy, cellular senescence is, on the one hand, intended to occur in tumor cells, as thereby the therapeutic outcome is improved, but might, on the other hand, also be induced unintentionally in non-tumor cells, causing inflammation, secondary tumors, and cancer relapse. Importantly, organismic aging leads to accumulation of senescent cells in tissues and organs of aged individuals. Senescent cells can occur transiently, e.g., during embryogenesis or during wound healing, with beneficial effects on tissue homeostasis and regeneration or accumulate chronically in tissues, which detrimentally affects the microenvironment by de- or transdifferentiation of senescent cells and their neighboring stromal cells, loss of tissue specific functionality, and induction of the senescence-associated secretory phenotype, an increased secretory profile consisting of pro-inflammatory and tissue remodeling factors. These factors shape their surroundings toward a pro-carcinogenic microenvironment, which fuels the development of aging-associated cancers together with the accumulation of mutations over time. We are presenting an overview of well-documented stress situations and signals, which induce senescence. Among them, oncogene-induced senescence and stress-induced premature senescence are prominent. New findings about the role of senescence in tumor biology are critically reviewed with respect to new suggestions for cancer therapy leveraging genetic and pharmacological methods to prevent senescence or to selectively kill senescent cells in tumors.

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Section: Upcoming Innovative Therapeutic Approachesmentioning

confidence: 99%

The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy

2017

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“…m 1 A was first documented more than 50 years ago (Dunn, 1961); later it was found to be a primordial RNA modification across the three major phylogenetic domains (Machnicka et al, 2013). In human cells, m 1 A is found at position 9 and 58 of human mitochondrial and cytoplasmic tRNAs, catalyzed by TRMT10C, TRMT61B and TRMT6/61A, respectively (Chujo and Suzuki, 2012; Ozanick et al, 2005; Vilardo et al, 2012); it is also present at position 1322 of 28S rRNA, catalyzed by NML (Waku et al, 2016). Its unique physicochemical property has also endowed m 1 A with pivotal roles in maintaining the proper structure and function of these ncRNAs (Roundtree et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Base-Resolution Mapping Reveals Distinct m1A Methylome in Nuclear- and Mitochondrial-Encoded Transcripts

et al. 2017

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SUMMARY Gene expression can be post-transcriptionally regulated via dynamic and reversible RNA modifications. N1-methyladenosine (m1A) is a recently identified mRNA modification; however, little is known about its precise location and biogenesis. Here, we develop a base-resolution m1A profiling method, based on m1A-induced misincorporation during reverse transcription, and report distinct classes of m1A methylome in the human transcriptome. m1A in 5′-UTR, particularly those at the mRNA cap, associate with increased translation efficiency. A different, small subset of m1A exhibit a GUUCRA tRNA-like motif, are evenly distributed in the transcriptome and are dependent on the methyltransferase TRMT6/61A. Additionally, we show that m1A is prevalent in the mitochondrial-encoded transcripts. Manipulation of m1A level via TRMT61B, a mitochondria-localizing m1A methyltransferase, demonstrates that m1A in mitochondrial mRNA interferes with translation. Collectively, our approaches reveal distinct classes of m1A methylome and provide a resource for functional studies of m1A-mediated epitranscriptomic regulation.

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“…It is well known that YTH domain-containing proteins play as m 6 A readers and can regulate mRNA metabolism 15,38,39 , but whether they can act as readers of other RNA modifications is unknown. We use the m 1 A probes derived from the native present m 1 A modification site of human 28S rRNA with stem and loop structure 40 , because they can be more easily and specifically recognized by intracellular reader protein. We found that nine proteins, including mitochondrial ATP synthase subunit alpha (ATP5A1), 78 kDa glucose-regulated protein (HSPA5), transcriptional activator protein Pur-alpha (PURA), heterogeneous nuclear ribonucleoprotein M (HNRNPM), ADP/ATP translocase 2 (SLC25A5), RNAbinding protein 28 (RBM28), poly(rC)-binding protein 1 (PCBP1), YTH domain-containing family protein 3 (YTHDF3), and ruvB-like 2 (RUVBL2), can interact with m 1 A-carrying RNA.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic m1A reader YTHDF3 inhibits trophoblast invasion by downregulation of m1A-methylated IGF1R

et al. 2020

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N 1-methyladenosine (m 1 A) is one of the important post-transcriptional modifications in RNA and plays an important role in promoting translation or decay of m 1 A-methylated messenger RNA (mRNA), but the "reader" protein and the exact biological role of m 1 A remain to be determined. Here, we identified that nine potential m 1 A "reader" proteins including YTH domain family and heterogeneous nuclear ribonucleoprotein by mass spectrometry, and among them, YTH domain-containing protein 3 (YTHDF3), could bind directly to m 1 A-carrying RNA. YTHDF3 was then identified to negatively regulate invasion and migration of trophoblast. Mechanistically, we found that the m 1 A "reader" YTHDF3 bound to certain m 1 A-methylated transcripts, such as insulin-like growth factor 1 receptor (IGF1R), with the combination of iCLIP-seq (individual-nucleotide resolution ultraviolet crosslinking and immunoprecipitation highthroughput sequencing) and m 1 A-seq. Furthermore, YTHDF3 could promote IGF1R mRNA degradation and thus inhibit IGF1R protein expression along with its downstream matrix metallopeptidase 9 signaling pathway, consequently decreasing migration and invasion of trophoblast. Thus, we demonstrated that YTHDF3 as an m 1 A reader decreased invasion and migration of trophoblast by inhibiting IGF1R expression. Our study outlines a new m 1 A epigenetic way to regulate the trophoblast activity, which suggests a novel therapeutic target for trophoblastassociated pregnancy disorders.

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NML-mediated rRNA base methylation links ribosomal subunit formation to cell proliferation in a p53-dependent manner

Cited by 85 publications

References 58 publications

The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy

The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy

Base-Resolution Mapping Reveals Distinct m1A Methylome in Nuclear- and Mitochondrial-Encoded Transcripts

Cytoplasmic m1A reader YTHDF3 inhibits trophoblast invasion by downregulation of m1A-methylated IGF1R

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