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9One striking characteristic of certain herpesviruses is their ability to induce rapid and 10 widespread RNA decay in order to gain access to host resources. This phenotype is induced by 11 viral endoribonucleases, including SOX in KSHV, muSOX in MHV68, BGLF5 in EBV and vhs in 12 HSV-1. Here, we performed comparative RNA-seq upon expression of these herpesviral 13 endonucleases in order to characterize their effect on the host transcriptome. Consistent with 14 previous reports, we found that approximately two thirds of transcripts are downregulated in 15 cells expressing any of these viral endonucleases. Among transcripts spared from degradation, 16we uncovered a cluster of transcripts that systematically escape degradation from all tested 17 endonucleases. Among these escapees, we identified C19ORF66 and reveal that like the 18 previously identified escapees, this transcript is protected from degradation by its 3'UTR. We 19 then show that C19ORF66, a known anti-viral protein, is a potent KSHV restriction factor, 20suggesting that its ability to escape viral cleavage may be an important component of the host 21 response to viral infection. Collectively, our comparative approach is a powerful tool to pinpoint 22 key regulators of the viral-host interplay and led us to uncover a novel KSHV regulator. 23 24 25 26 All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. . https://doi.org/10.1101/506410 doi: bioRxiv preprint characterized by a defined sequence motif (19) rendering it difficult to identify new escaping 48 transcripts by traditional sequence search. Consequently, the host vs. viral endonuclease 49 dichotomy to only defining characteristic of this novel type of RNA element. 50 All rights reserved. No reuse allowed without permission.

Submission of an original paper with copyright agreement and authorship responsibility.I (corresponding author) certify that I have participated sufficiently in the conception and design of this work and the analysis of the data (wherever applicable), as well as the writing of the manuscript, to take public responsibility for it. I believe the manuscript represents valid work. I have reviewed the final version of the manuscript and approve it for publication. Neither has the manuscript nor one with substantially similar content under my authorship been published nor is being considered for publication elsewhere, except as described in an attachment. Furthermore I attest that I shall produce the data upon which the manuscript is based for examination by the editors or their assignees, if requested.Thanking you.