RT Journal Article SR Electronic T1 Caspases switch off m6A RNA modification pathway to reactivate a ubiquitous human tumor virus JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.11.12.377127 DO 10.1101/2020.11.12.377127 A1 Kun Zhang A1 Yucheng Zhang A1 Jun Wan A1 Renfeng Li YR 2020 UL http://biorxiv.org/content/early/2020/11/13/2020.11.12.377127.abstract AB The methylation of RNA at the N6 position of adenosine (m6A) orchestrates multiple biological processes to control development, differentiation, and cell cycle, as well as various aspects of the virus life cycle. How the m6A RNA modification pathway is regulated to finely tune these processes remains poorly understood. Here, we discovered the m6A reader YTHDF2 as a caspase substrate via proteome-wide prediction, followed by in vitro and in vivo experimental validations. We further demonstrated that cleavage-resistant YTHDF2 blocks, while cleavage-mimicking YTHDF2 fragments promote, the replication of a common human oncogenic virus, Epstein-Barr virus (EBV). Intriguingly, our study revealed a feedback regulation between YTHDF2 and caspase-8 via m6A modification of CASP8 mRNA and YTHDF2 cleavage during EBV replication. Further, we discovered that caspases cleave multiple components within the m6A RNA modification pathway to benefit EBV replication. Together, our study establishes caspase disarming the m6A RNA modification machinery in fostering EBV reactivation.Competing Interest StatementThe authors have declared no competing interest.