SRSF2 plays an unexpected role as reader of m 5 C on mRNA, linking epitranscriptomics to cancer.

A common mRNA modification is 5-methylcytosine (m ⁵ C), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m ⁵ C and impaired SRSF2 m ⁵ C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m ⁵ C recognition and the impact of the prevalent leukemia-associated mutation SRSF2 ^P95H . We show that SRSF2 binding and m ⁵ C colocalize within transcripts. Furthermore, knocking down the m ⁵ C writer NSUN2 decreases mRNA m ⁵ C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2 ^P95H mutation impairs the ability of the protein to read m ⁵ C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m ⁵ C hypomethylation and, combined with SRSF2 ^P95H , predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver.
Competing Interests: Declaration of interests F.F. is a co-founder of Epics Therapeutics (Gosselies, Belgium).
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