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Sequence- and structure-specific cytosine-5 mRNA methylation by NSUN6
Tommaso Selmi1, Shobbir Hussain2, Sabine Dietmann3
1Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
Nucleic Acids Research
|December 17, 2020
Summary
This study identifies NSUN6 as a key mRNA methyltransferase. NSUN6 targets specific 3'UTR regions, enhancing translation and potentially controlling termination fidelity, with implications for cancer.
Area of Science:
- Molecular Biology
- Epigenetics
- RNA Biology
Background:
- N6-methyladenosine (m6A) is a common RNA modification, but the role of 5-methylcytidine (m5C) is less understood.
- Investigating rarer RNA modifications like m5C is crucial for understanding mRNA regulation.
Purpose of the Study:
- To map m5C modifications in the human transcriptome.
- To identify the specific enzyme responsible for m5C methylation on mRNA.
- To elucidate the functional consequences of NSUN6-mediated m5C methylation.
Main Methods:
- Methylation-dependent individual-nucleotide resolution cross-linking and immunoprecipitation (miCLIP) combined with RNA bisulfite sequencing.
- Identification of NSUN6 as an mRNA methyltransferase.
- Knockout and rescue experiments in cells.
- Ribosome profiling.
Main Results:
- NSUN6 specifically targets the CTCCA motif in mRNA 3'UTRs, often within hairpin structures.
- NSUN6-mediated m5C methylation enhances mRNA and translation levels.
- Methylation by NSUN6 correlates with translation termination.
- NSUN6 is downregulated in human tumors and linked to better patient outcomes in some cancers.
Conclusions:
- NSUN6 is a novel mRNA methyltransferase with a specific targeting mechanism.
- NSUN6-mediated m5C modification plays a role in translation termination fidelity and mRNA regulation.
- NSUN6 has potential as a biomarker and therapeutic target in cancer.