Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus

Jiawei Zhao, Eunice E. Lee, Jiwoong Kim, Rong Yang, Bahir Chamseddin, Chunyang Ni, Elona Gusho, Yang Xie, Cheng-Ming Chiang, Michael Buszczak, Xiaowei Zhan, Laimonis Laimins and Richard C. Wang ()
Additional contact information
Jiawei Zhao: UT Southwestern Medical Center
Eunice E. Lee: UT Southwestern Medical Center
Jiwoong Kim: UT Southwestern Medical Center
Rong Yang: UT Southwestern Medical Center
Bahir Chamseddin: UT Southwestern Medical Center
Chunyang Ni: UT Southwestern Medical Center
Elona Gusho: Northwestern University
Yang Xie: UT Southwestern Medical Center
Cheng-Ming Chiang: UT Southwestern Medical Center
Michael Buszczak: UT Southwestern Medical Center
Xiaowei Zhan: UT Southwestern Medical Center
Laimonis Laimins: Northwestern University
Richard C. Wang: UT Southwestern Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Single-stranded circular RNAs (circRNAs), generated through ‘backsplicing’, occur more extensively than initially anticipated. The possible functions of the vast majority of circRNAs remain unknown. Virus-derived circRNAs have recently been described in gamma-herpesviruses. We report that oncogenic human papillomaviruses (HPVs) generate circRNAs, some of which encompass the E7 oncogene (circE7). HPV16 circE7 is detectable by both inverse RT-PCR and northern blotting of HPV16-transformed cells. CircE7 is N6-methyladenosine (m6A) modified, preferentially localized to the cytoplasm, associated with polysomes, and translated to produce E7 oncoprotein. Specific disruption of circE7 in CaSki cervical carcinoma cells reduces E7 protein levels and inhibits cancer cell growth both in vitro and in tumor xenografts. CircE7 is present in TCGA RNA-Seq data from HPV-positive cancers and in cell lines with only episomal HPVs. These results provide evidence that virus-derived, protein-encoding circular RNAs are biologically functional and linked to the transforming properties of some HPV.

Date: 2019
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DOI: 10.1038/s41467-019-10246-5

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