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<p>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 <i>cis</i>- and <i>trans</i>-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.</p>

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Noncanonical circRNA biogenesis driven by alpha and gamma herpesviruses

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月3日

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  • Sarah E Dremel,
  • Vishal N Koparde,
  • Jesse H Arbuckle,
  • Chad H Hogan,
  • Thomas M Kristie,
  • Laurie T Krug,
  • Nicholas K Conrad,
  • Joseph M Ziegelbauer

摘要

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.