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

• DOI: 10.1038/s41467-019-10246-5
• Publication Date: 2019-05-24T10:03:50Z
• Authors: 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; Richard C. Wang
• Keywords: Human papillomavirus 16; Sequence Analysis, RNA; Science; Papillomavirus E7 Proteins; Q; Datasets as Topic; Uterine Cervical Neoplasms; RNA, Circular; Xenograft Model Antitumor Assays; Article; 3. Good health; Mice; Cell Transformation, Neoplastic; Mice, Inbred NOD; Cell Line, Tumor; Gene Knockdown Techniques; Polyribosomes; Host-Pathogen Interactions; Animals; Humans; RNA; RNA, Viral; Female; RNA, Small Interfering

AbstractSingle-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.