Identification and characterization of Varicella Zoster Virus circular RNA in lytic infection

Shaomin Yang, Di Cao, Dabbu Kumar Jaijyan, Mei Wang, Jian Liu, Ruth Cruz-cosme, Songbin Wu, Jiabin Huang, Mulan Zeng, Xiaolian Liu, Wuping Sun, Donglin Xiong, Qiyi Tang (), Lizu Xiao () and Hua Zhu ()
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Shaomin Yang: Huazhong University of Science and Technology Union Shenzhen Hospital
Di Cao: Huazhong University of Science and Technology Union Shenzhen Hospital
Dabbu Kumar Jaijyan: Rutgers University
Mei Wang: Jinan University
Jian Liu: Minnan Normal University
Ruth Cruz-cosme: Howard University College of Medicine
Songbin Wu: Huazhong University of Science and Technology Union Shenzhen Hospital
Jiabin Huang: Huazhong University of Science and Technology Union Shenzhen Hospital
Mulan Zeng: Rutgers University
Xiaolian Liu: Jinan University
Wuping Sun: Huazhong University of Science and Technology Union Shenzhen Hospital
Donglin Xiong: Huazhong University of Science and Technology Union Shenzhen Hospital
Qiyi Tang: Howard University College of Medicine
Lizu Xiao: Huazhong University of Science and Technology Union Shenzhen Hospital
Hua Zhu: Rutgers University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract This study investigates the role of circular RNAs (circRNAs) in the context of Varicella-Zoster Virus (VZV) lytic infection. We employ two sequencing technologies, short-read sequencing and long-read sequencing, following RNase R treatment on VZV-infected neuroblastoma cells to identify and characterize both cellular and viral circRNAs. Our large scanning analysis identifies and subsequent experiments confirm 200 VZV circRNAs. Moreover, we discover numerous VZV latency-associated transcripts (VLTs)-like circRNAs (circVLTslytic), which contain multiple exons and different isoforms within the same back-splicing breakpoint. To understand the functional significance of these circVLTslytic, we utilize the Bacteria Artificial Chromosome system to disrupt the expression of viral circRNAs in genomic DNA location. We reveal that the sequence flanking circVLTs’ 5’ splice donor plays a pivotal role as a cis-acting element in the formation of circVLTslytic. The circVLTslytic is dispensable for VZV replication, but the mutation downstream of circVLTslytic exon 5 leads to increased acyclovir sensitivity in VZV infection models. This suggests that circVLTslytic may have a role in modulating the sensitivity to antiviral treatment. The findings shed new insight into the regulation of cellular and viral transcription during VZV lytic infection, emphasizing the intricate interplay between circRNAs and viral processes.

Date: 2024
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DOI: 10.1038/s41467-024-49112-4

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