Noncanonical circRNA biogenesis driven by alpha and gamma herpesviruses

Author:

Dremel, Sarah E

Koparde,Vishal [ORCID]

Arbuckle, Jesse H [ORCID]

Hogan, Chad H [ORCID]

Kristie, Thomas M [ORCID]

Krug, Laurie T [ORCID]

Conrad, Nicholas K [ORCID]

Ziegelbauer, Joseph M [ORCID]
Author Address

HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA., Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, 22908, USA., CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Advanced Biomedical Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD, 21701, USA., Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, 20892, USA., Graduate Program in Genetics, Stony Brook University, Stony Brook, NY, 11794, USA., Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Department of Microbiology, UT Southwestern Medical Center, Dallas, TX, 75390, USA., HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892, USA. ziegelbauerjm@nih.gov.,

Abstract:

Herpesviruses require the host transcriptional machinery, inducing significant changes in gene expression to prioritize viral transcripts. We examined alpha- and gamma-herpesvirus alterations to a type of alternative splicing, namely circular RNA (circRNA) synthesis. We developed "Circrnas in Host And viRuses anaLysis pIpEline" (CHARLIE) to facilitate viral profiling. This method identified thousands of back-splicing variants, including circRNA common to lytic and latent phases of infection. Ours is the first report of Herpes Simplex Virus-1 circRNAs, including species derived from ICP0 and the latency-associated transcript. We characterized back-splicing cis- and trans-elements, and found viral circRNAs resistant to spliceosome perturbation and lacking canonical splice donor-acceptors. Subsequent loss-of-function studies of host RNA ligases (RTCB, RLIG1) revealed instances of decreased viral back splicing. Using eCLIP and 4sU-Sequencing, we determined that the KSHV RNA-binding protein, ORF57, enhanced synthesis for a subset of viral and host circRNAs. Our work explores unique splicing mechanisms driven by lytic infection, and identifies a class of transcripts with the potential to function in replication, persistence, or tumorigenesis. © 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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