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The post-translational modifications and translation-regulatory role of METTL14 in 5-fluorouracil-resistant colorectal cancer [Ribo-seq]

ABSTRACT: The post-translational modifications and translation-regulatory role of METTL14 in 5-fluorouracil-resistant colorectal cancer [Ribo-seq]

PROVIDER: PRJNA907315 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22484279_1.fastq.gz	Fastqsanger.gz
	SRR22484279_2.fastq.gz	Fastqsanger.gz
	SRR22484280_1.fastq.gz	Fastqsanger.gz
	SRR22484280_2.fastq.gz	Fastqsanger.gz
	SRR22484281_1.fastq.gz	Fastqsanger.gz

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The post-translational modifications and translation-regulatory role of METTL14 in 5-fluorouracil-resistant colorectal cancer [Ribo-seq]

Project description:5-fluorouracil (5‑FU) based chemotherapy is the first-line chemotherapy scheme for CRC, whereas acquired drug resistance poses a huge obstacle to curing CRC patients and the mechanism is still obscure. METTL14 is a core subunit of the m6A methyltransferase complex and has been reported to regulate the drug resistance of cancers. Here, we demonstrated that METTL14 is significantly downregulated in 5-FU-resistant CRC and METTL14 overexpression inhibits the proliferation and 5-FU resistance of CRC cells in vitro and in vivo. In addition, we found that MIB1 catalyzes the K63-linked ubiquitination of METTL14 and induces its degradation through the autolysosome pathway, while AURKA-mediated phosphorylation enhances METTL14 stability by inhibiting its ubiquitination. Moreover, we first discovered that METTL14 functions in 5-FU-resistant CRC cells by directly participating in the translation initiation of non-m6A-modified mRNAs independently of METTL3, rather than cooperating with METTL3 to methylate adenosine residues of targets. Further analysis indicated that METTL14 regulates the cell cycle process in 5-FU-resistant CRC cells. Collectively, our study not only identified METTL14 as a potential therapeutic target for 5-FU resistance in CRC but also revealed a novel translation-facilitating role of METTL14.

2023-12-01 | GSE219172 | GEO

The post-translational modifications and translation-regulatory role of METTL14 in 5-fluorouracil-resistant colorectal cancer

Project description:The post-translational modifications and translation-regulatory role of METTL14 in 5-fluorouracil-resistant colorectal cancer

| PRJNA907307 | ENA

The post-translational modifications and translation-regulatory role of METTL14 in 5-fluorouracil-resistant colorectal cancer [mRNA-seq]

2023-12-01 | GSE219171 | GEO

The post-translational modifications and translation-regulatory role of METTL14 in 5-fluorouracil-resistant colorectal cancer [mRNA-seq]

Project description:The post-translational modifications and translation-regulatory role of METTL14 in 5-fluorouracil-resistant colorectal cancer [mRNA-seq]

| PRJNA907308 | ENA

The impact of METTL14 knockdown on gene expressions and m6A modifications in breast cancer

Project description:We previously found that the downregulation of METTL14 played a crucial role in maintaining breast cancer stem-like properties. The present study aims to explore the impact of METTL14 knockdown on gene expressions and m6A modifications related to stemness in order to elucidate the underlying mechanisms.

2024-11-27 | GSE245282 | GEO

Specific sDMA Modifications on the RGG/RG Motif of METTL14 Regulate Its Function in AML

Project description:Protein arginine methylations are crucial post-translational modifications (PTMs) in eukaryotes, playing a significant regulatory role in diverse biological processes. Different forms of arginine methylations are known to co-exist within densely modified arginine-rich protein regions. However, pinpointing the precise pattern of arginine methylation and their functional implications have been challenging. In this study, we employed high-resolution mass spectrometry and in vitro enzyme reactions to uncover that the RGG/RG motifs located in the C-terminal region of METTL14 undergo both asymmetric and symmetric dimethylations (aDMA and sDMA). Specifically, PRMT5 catalyses the symmetric dimethylation of residues R425 and R445 within the extensively methylated region of METTL14, whereas PRMT1 demonstrates a broader substrate specificity. Our results indicate that mutating R425 and R445 to lysines reduces the catalytic efficiency of the METTL3:METTL14 complex, implying that sDMA modifications at these residues are important for MELL14’s function. Moreover, our findings underscore the role of sDMA modifications on METTL14 in regulating m6A-specific gene expression, including BRD4, SP1, and c-MYC, in acute myeloid leukaemia (AML) cell lines. Finally, the proliferation of AML cells is more sensitive to the combined inhibition of METTL3 and PRMT5 activity than inhibiting either alone. In summary, our study delineates the methylation landscape of the C terminal region of METTL14 and shows that sDMA modifications at residues R425 and R445 modulate the m6A deposition activity of the methyltransferase complex. These insights suggest that sDMA modifications in METTL14 could represent a promising therapeutic target for the treatment of AML.

2024-08-05 | PXD054570 |

Mettl14 deficiency promotes Fam32a expression via m6A modifications to facilitate the hepatocyte G1/S transition

Project description:Mettl14, a key component of the m6A methyltransferase complex, plays a crucial role in regulating mRNA stability and splicing. Reduced expression of Mettl14 is associated with hepatocellular carcinoma and liver regeneration, yet the molecular mechanisms by which it regulates the hepatocyte cell cycle remain unclear. Using RNA-Seq and MeRIP-Seq in liver-specific Mettl14 knockout mice, we found that Mettl14 deficiency stabilizes Fam32a mRNA through m6A modifications, resulting in increased Fam32a protein levels. Elevated Fam32a expression accelerates the G1/S transition by modulating Cdkn1a splicing, specifically downregulating its variant 2. These findings uncover a novel m6A-dependent mechanism that regulates hepatocyte cell cycle progression and highlight the previously unrecognized role of Fam32a in promoting the G1/S transition.

2025-03-31 | GSE293314 | GEO

Cancer Mutations Rewire the RNA Methylation Specificity of METTL3-METTL14

Project description:Chemical modification of RNAs is important for post-transcriptional gene regulation. The METTL3-METTL14 complex generates most N6-methyladenosine (m6A) modifications in mRNAs, and dysregulated methyltransferase expression has been linked to numerous cancers. Here we show that m6A modification location, rather than the overall modification level, can impact oncogenesis. A gain-of-function missense mutation found in cancer patients, METTL14R298P, promotes malignant cell growth in culture and in transgenic mice. The mutant methyltransferase preferentially modifies noncanonical sites and transforms gene expression without increasing global m6A levels in mRNAs. The altered substrate specificity is intrinsic to METTL3-METTL14, helping us to propose a structural model for how the METTL3-METTL14 complex detects RNA sequences. Together, our work highlights that m6A location is important for function and that noncanonical methylation sites may impact aberrant gene expression and oncogenesis.

2024-12-21 | PXD039447 | Pride

Arginine methylation of METTL14 promotes RNA N6-methyladenosine modification

Project description:Both mRNA and proteins can be modified through addition of methyl groups. For example, addition of N6-methyladenosine (m6A) to mRNAs is critical for human development and health. Post-translational methylation of proteins can impact the dynamic regulation of enzymatic activity. Here we sought to explore the nexus of transcriptional and post-translational methylation by studying the role of methylation of the core methyltransferase METTL3/METTL14 in m6A regulation. We found by mass spectrometry that METTL14 arginine 255 (R255) is methylated (R255me). Global mRNA m6A levels were greatly decreased in METTL14 R255K mutant mouse embryonic stem cells (mESCs). We further found that R255me greatly enhances the interaction of METTL3/METTL14 with WTAP and promotes the binding of the complex to substrate RNA.

2021-05-14 | GSE164047 | GEO

Post-translational modifications of SNAP29

Project description:To identify the post-translational modifications of SNAP29

2025-12-24 | PXD072394 |