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Methylation regulates HCV genome translation

Hepatitis C virus (HCV) causes chronic liver infections that can result in organ damage and may even progress to cancer. Translation of the HCV RNA genome is dependent on an internal ribosome entry site (IRES), in which multiple N6-methyladenosine (m6A) modifications have been detected. Kim and Siddiqui report that methylation of one of these adenosines regulates HCV RNA translation initiation. Adenosine 331 mutation reduced viral RNA and protein, and m6A modification increased IRES-mediated translation. This effect was mediated by the m6A reader protein YTHDC2, including both its m6A-binding and RNA helicase activity. YTHDC2 interacted with the La antigen, a cellular protein required for HCV IRES-mediated translation. Adenosine 331 mutation reduced this interaction and abolished La protein induction of HCV IRES-mediated translation. Thus, m6A modification of the HCV IRES regulates the viral life cycle and could represent a novel therapeutic target.


Original article

  1. Kim, G.-W. & Siddiqui, A. N6-methyladenosine modification of HCV RNA genome regulates cap-independent IRES-mediated translation via YTHDC2 recognition. Proc. Natl Acad. Sci. USA 118, e2022024118 (2021)

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Correspondence to Grant Otto.

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Otto, G. Methylation regulates HCV genome translation. Nat Rev Microbiol 19, 284 (2021).

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