title: Viral Nucleases Induce an mRNA Degradation-Transcription Feedback Loop in Mammalian Cells.
abstract: Gamma-herpesviruses encode a cytoplasmic mRNA-targeting endonuclease, SOX, that cleaves most cellular mRNAs. Cleaved fragments are subsequently degraded by the cellular 5'-3' mRNA exonuclease Xrn1, thereby suppressing cellular gene expression and facilitating viral evasion of host defenses. We reveal that mammalian cells respond to this widespread cytoplasmic mRNA decay by altering RNA Polymerase II (RNAPII) transcription in the nucleus. Measuring RNAPII recruitment to promoters and nascent mRNA synthesis revealed that the majority of affected genes are transcriptionally repressed in SOX-expressing cells. The transcriptional feedback does not occur in response to the initial viral endonuclease-induced cleavage, but instead to degradation of the cleaved fragments by cellular exonucleases. In particular, Xrn1 catalytic activity is required for transcriptional repression. Notably, viral mRNA transcription escapes decay-induced repression, and this escape requires Xrn1. Collectively, these results indicate that mRNA decay rates impact transcription and that gamma-herpesviruses use this feedback mechanism to facilitate viral gene expression.
authors.affiliation: Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Abernathy
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gilbertson
authors.affiliation: QB3 Computational Genomics Resource Laboratory, University of California, Berkeley, CA 94720, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Alla
authors.affiliation: Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. Electronic address: glaunsinger@berkeley.edu.
authors.forename: Britt
authors.initials: B
authors.lastname: Glaunsinger
mesh_terms: D002460:Cell Line; D005095:Exoribonucleases / Q000378:metabolism; D005246:Feedback; D018142:Gammaherpesvirinae / Q000201:enzymology*; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors; D020871:RNA Stability; D012260:Ribonucleases / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic
chemical_list: D008869:Microtubule-Associated Proteins; D012319:RNA Polymerase II; D005095:Exoribonucleases; D012260:Ribonucleases; C470512:XRN1 protein, human