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

ABSTRACT: METTL16 has recently been identified as an RNA methyltransferase responsible for the deposition of N⁶-methyladenosine (m⁶A) in a few transcripts. Whether METTL16 methylates a large set of transcripts, similar to METTL3 and METTL14, remains unclear. Here we show that METTL16 exerts both methyltransferase activity-dependent and -independent functions in gene regulation. In the cell nucleus, METTL16 functions as an m⁶A writer to deposit m⁶A into hundreds of its specific messenger RNA targets. In the cytosol, METTL16 promotes translation in an m⁶A-independent manner. More specifically, METTL16 directly interacts with the eukaryotic initiation factors 3a and -b as well as ribosomal RNA through its Mtase domain, thereby facilitating the assembly of the translation-initiation complex and promoting the translation of over 4,000 mRNA transcripts. Moreover, we demonstrate that METTL16 is critical for the tumorigenesis of hepatocellular carcinoma. Collectively, our studies reveal previously unappreciated dual functions of METTL16 as an m⁶A writer and a translation-initiation facilitator, which together contribute to its essential function in tumorigenesis.

SUBMITTER: Su R

PROVIDER: S-EPMC9070413 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Su Rui R Dong Lei L Li Yangchan Y Gao Min M He P Cody PC Liu Wei W Wei Jiangbo J Zhao Zhicong Z Gao Lei L Han Li L Deng Xiaolan X Li Chenying C Prince Emily E Tan Brandon B Qing Ying Y Qin Xi X Shen Chao C Xue Meilin M Zhou Keren K Chen Zhenhua Z Xue Jianhuang J Li Wei W Qin Hanjun H Wu Xiwei X Sun Miao M Nam Yunsun Y Chen Chun-Wei CW Huang Wendong W Horne David D Rosen Steven T ST He Chuan C Chen Jianjun J

Nature cell biology 20220210 2

METTL16 has recently been identified as an RNA methyltransferase responsible for the deposition of N6-methyladenosine (m6A) in a few transcripts. Whether METTL16 methylates a large set of transcripts, similar to METTL3 and METTL14, remains unclear. Here we show that METTL16 exerts both methyltransferase activity-dependent and -independent functions in gene regulation. In the cell nucleus, METTL16 functions as an m6A writer to deposit m6A into hundreds ...[more]

PMID: 35145225

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Project description:BackgroundPoly C Binding Protein 1 (PCBP1) is an RNA-binding protein that binds and regulates translational activity of subsets of cellular mRNAs. Depletion of PCBP1 is implicated in various carcinomas, but the underlying mechanism in tumorigenesis remains elusive.MethodsWe performed a transcriptome-wide screen to identify novel bounding mRNA of PCBP1. The bind regions between PCBP1 with target mRNA were investigated by using point mutation and luciferase assay. Cell proliferation, cell cycle, tumorigenesis and cell apoptosis were also evaluated in ovary and colon cancer cell lines. The mechanism that PCBP1 affects p27 was analyzed by mRNA stability and ribosome profiling assays. We analyzed PCBP1 and p27 expression in ovary, colon and renal tumor samples and adjacent non-tumor tissues using RT-PCR, Western Blotting and immunohistochemistry. The prognostic significance of PCBP1 and p27 also analyzed using online databases.ResultsWe identified cell cycle inhibitor p27Kip1 (p27) as a novel PCBP1-bound transcript. We then demonstrated that binding of PCBP1 to p27 3'UTR via its KH1 domain mainly stabilizes p27 mRNA, while enhances its translation to fuel p27 expression, prior to p27 protein degradation. The upregulated p27 consequently inhibits cell proliferation, cell cycle progression and tumorigenesis, whereas promotes cell apoptosis under paclitaxel treatment. Conversely, knockdown of PCBP1 in turn compromises p27 mRNA stability, leading to lower p27 level and tumorigenesis in vivo. Moreover, forced depletion of p27 counteracts the tumor suppressive ability of PCBP1 in the same PCBP1 over-expressing cells. Physiologically, we showed that decreases of both p27 mRNA and its protein expressions are well correlated to PCBP1 depletion in ovary, colon and renal tumor samples, independent of the p27 ubiquitin ligase Skp2 level. Correlation of PCBP1 with p27 is also found in the tamoxifen, doxorubincin and lapatinib resistant breast cancer cells of GEO database.ConclusionOur results thereby indicate that loss of PCBP1 expression firstly attenuates p27 expression at post-transcriptional level, and subsequently promotes carcinogenesis. PCBP1 could be used as a diagnostic marker to cancer patients.

Dataset Information

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

Publications

METTL16 exerts an m<sup>6</sup>A-independent function to facilitate translation and tumorigenesis.

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