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A cohort of mRNAs undergo high-stoichiometry NSUN6-mediated site-specific m5C modification

Yuan-Yuan Zhang1, Cai-Tao Li1,2, You-Jia Zhou1

  • 1School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

Nature Communications
|July 4, 2025
PubMed

Insights

NSUN6 enzyme independently modifies mRNA with 5-methylcytidine (m5C), promoting breast cancer cell migration. This m5C modification enhances mRNA stability, offering potential for therapeutic applications.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Internal mRNA modifications regulate cellular processes but often lack dedicated enzymes.
  • The roles of most mRNA modifications, beyond m6A, are debated due to reliance on tRNA-modifying enzymes and complex interactions.

Purpose of the Study:

  • To biochemically validate NSUN6 as an independent catalyst for mRNA 5-methylcytidine (m5C) modification.
  • To investigate the role of NSUN6-mediated mRNA m5C in breast cancer cell migration.
  • To explore the therapeutic potential of mRNA m5C modifications.

Main Methods:

  • Biochemical assays to characterize NSUN6 activity on mRNA and tRNA substrates.
  • Site-directed mutagenesis to differentiate NSUN6's catalytic roles.
  • Analysis of mRNA m5C modification levels, mRNA stability, and protein binding (YBX1, YBX3) in cancer cells.

Main Results:

  • NSUN6 directly catalyzes m5C formation on mRNA by recognizing specific sequence and structural motifs.
  • NSUN6-mediated mRNA m5C modification promotes breast cancer cell migration.
  • m5C modification stabilizes target mRNAs, including those involved in cell migration, via readers like YBX1 and YBX3.
  • Site-specific m5C introduction enhances the stability of therapeutic mRNAs.

Conclusions:

  • NSUN6 is a key enzyme for mRNA m5C modification, independent of tRNA modification pathways.
  • NSUN6-driven mRNA m5C plays a significant role in promoting breast cancer cell migration.
  • Targeting mRNA m5C modification holds promise for developing novel cancer therapies and enhancing mRNA-based therapeutics.

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