Molecular Cell: SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer (Gupta Lab)

Hai-Li Ma 1 14, Martin Bizet 1 14, Christelle Soares Da Costa 1 14, Frédéric Murisier 1, Eric James de Bony 1 8, Meng-Ke Wang 2, Akihide Yoshimi 3 9, Kuan-Ting Lin 7, Kristin M. Riching 4, Xing Wang 2, John I. Beckman 5, Shailee Arya 5, Nathalie Droin 6, Emilie Calonne 1, Bouchra Hassabi 1, Qing-Yang Zhang 2 10, Ang Li 2 11, Pascale Putmans 1, Lionel Malbec 1, Céline Hubert 1…François Fuks 1 15

Highlights
RSF2 preferentially binds m5C-marked mRNA, whereas SRSF2P95H mutant impairs binding
NSUN2 depletion reduces mRNA m5C levels and alters SRSF2 RNA binding and splicing
NSUN2 loss and SRSF2P95H alter SRSF2 binding to key leukemia-related transcripts
In leukemia patients, low NSUN2 levels and SRSF2P95H mutation predict poor outcomes

Summary
A common mRNA modification is 5-methylcytosine (m5C), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m5C and impaired SRSF2 m5C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m5C recognition and the impact of the prevalent leukemia-associated mutation SRSF2P95H. We show that SRSF2 binding and m5C colocalize within transcripts. Furthermore, knocking down the m5C writer NSUN2 decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2P95H mutation impairs the ability of the protein to read m5C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m5C hypomethylation and, combined with SRSF2P95H, predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver.

Keywords

• RNA modification
• SRSF2
• SRSF2P95H
• NSUN2
• m5C
• RNA splicing
• leukemia
• cancer
• epitranscriptomics
• RNA methylation

Read Full Text

Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to understanding its causes, and accelerate the translation of knowledge into novel therapies. Greehey CCRI strives to have a national and global impact on childhood cancer by discovering, developing, and disseminating new scientific knowledge. Our mission consists of three key areas — research, clinical, and education.

Stay connected with the Greehey CCRI on Facebook, Twitter, LinkedIn, and Instagram.