SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer

Hai Li Ma; Martin Bizet; Christelle Soares Da Costa; Frédéric Murisier; Eric James de Bony; Meng Ke Wang; Akihide Yoshimi; Kuan Ting Lin; Kristin M. Riching; Xing Wang; John I. Beckman; Shailee Arya; Nathalie Droin; Emilie Calonne; Bouchra Hassabi; Qing Yang Zhang; Ang Li; Pascale Putmans; Lionel Malbec; Céline Hubert; Jie Lan; Frédérique Mies; Ying Yang; Eric Solary; Danette L. Daniels; Yogesh K. Gupta; Rachel Deplus; Omar Abdel-Wahab; Yun Gui Yang; François Fuks

doi:10.1016/j.molcel.2023.11.003

SRSF2 plays an unexpected role as reader of m⁵C on mRNA, linking epitranscriptomics to cancer

Hai Li Ma, Martin Bizet, Christelle Soares Da Costa, Frédéric Murisier, Eric James de Bony, Meng Ke Wang, Akihide Yoshimi, Kuan Ting Lin, Kristin M. Riching, Xing Wang, John I. Beckman, Shailee Arya, Nathalie Droin, Emilie Calonne, Bouchra Hassabi, Qing Yang Zhang, Ang Li, Pascale Putmans, Lionel Malbec, Céline HubertJie Lan, Frédérique Mies, Ying Yang, Eric Solary, Danette L. Daniels, Yogesh K. Gupta, Rachel Deplus, Omar Abdel-Wahab, Yun Gui Yang, François Fuks

Producción científica: Article › revisión exhaustiva

8 Citas (Scopus)

Resumen

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 SRSF2^P95H. 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 SRSF2^P95H 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 SRSF2^P95H, predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver.

Idioma original	English (US)
Páginas (desde-hasta)	4239-4254.e10
Publicación	Molecular Cell
Volumen	83
N.º	23
DOI	https://doi.org/10.1016/j.molcel.2023.11.003
Estado	Published - dic 7 2023

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2023.11.003

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Ma, H. L., Bizet, M., Soares Da Costa, C., Murisier, F., de Bony, E. J., Wang, M. K., Yoshimi, A., Lin, K. T., Riching, K. M., Wang, X., Beckman, J. I., Arya, S., Droin, N., Calonne, E., Hassabi, B., Zhang, Q. Y., Li, A., Putmans, P., Malbec, L., ... Fuks, F. (2023). SRSF2 plays an unexpected role as reader of m⁵C on mRNA, linking epitranscriptomics to cancer. Molecular Cell, 83(23), 4239-4254.e10. https://doi.org/10.1016/j.molcel.2023.11.003

Ma, HL, Bizet, M, Soares Da Costa, C, Murisier, F, de Bony, EJ, Wang, MK, Yoshimi, A, Lin, KT, Riching, KM, Wang, X, Beckman, JI, Arya, S, Droin, N, Calonne, E, Hassabi, B, Zhang, QY, Li, A, Putmans, P, Malbec, L, Hubert, C, Lan, J, Mies, F, Yang, Y, Solary, E, Daniels, DL, Gupta, YK, Deplus, R, Abdel-Wahab, O, Yang, YG & Fuks, F 2023, 'SRSF2 plays an unexpected role as reader of m⁵C on mRNA, linking epitranscriptomics to cancer', Molecular Cell, vol. 83, n.º 23, pp. 4239-4254.e10. https://doi.org/10.1016/j.molcel.2023.11.003

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title = "SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer",

abstract = "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 = "NSUN2, RNA methylation, RNA modification, RNA splicing, SRSF2, cancer, epitranscriptomics, leukemia, mC",

author = "Ma, {Hai Li} and Martin Bizet and {Soares Da Costa}, Christelle and Fr{\'e}d{\'e}ric Murisier and {de Bony}, {Eric James} and Wang, {Meng Ke} and Akihide Yoshimi and Lin, {Kuan Ting} and Riching, {Kristin M.} and Xing Wang and Beckman, {John I.} and Shailee Arya and Nathalie Droin and Emilie Calonne and Bouchra Hassabi and Zhang, {Qing Yang} and Ang Li and Pascale Putmans and Lionel Malbec and C{\'e}line Hubert and Jie Lan and Fr{\'e}d{\'e}rique Mies and Ying Yang and Eric Solary and Daniels, {Danette L.} and Gupta, {Yogesh K.} and Rachel Deplus and Omar Abdel-Wahab and Yang, {Yun Gui} and Fran{\c c}ois Fuks",

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doi = "10.1016/j.molcel.2023.11.003",

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T1 - SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer

AU - Ma, Hai Li

AU - Bizet, Martin

AU - Soares Da Costa, Christelle

AU - Murisier, Frédéric

AU - de Bony, Eric James

AU - Wang, Meng Ke

AU - Yoshimi, Akihide

AU - Lin, Kuan Ting

AU - Riching, Kristin M.

AU - Wang, Xing

AU - Beckman, John I.

AU - Arya, Shailee

AU - Droin, Nathalie

AU - Calonne, Emilie

AU - Hassabi, Bouchra

AU - Zhang, Qing Yang

AU - Li, Ang

AU - Putmans, Pascale

AU - Malbec, Lionel

AU - Hubert, Céline

AU - Lan, Jie

AU - Mies, Frédérique

AU - Yang, Ying

AU - Solary, Eric

AU - Daniels, Danette L.

AU - Gupta, Yogesh K.

AU - Deplus, Rachel

AU - Abdel-Wahab, Omar

AU - Yang, Yun Gui

AU - Fuks, François

PY - 2023/12/7

Y1 - 2023/12/7

N2 - 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.

AB - 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.

KW - NSUN2

KW - RNA methylation

KW - RNA modification

KW - RNA splicing

KW - SRSF2

KW - cancer

KW - epitranscriptomics

KW - leukemia

KW - mC

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DO - 10.1016/j.molcel.2023.11.003

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SN - 1097-2765

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JO - Molecular Cell

JF - Molecular Cell

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