A novel HPV16 splicing enhancer critical for viral oncogene expression and cell immortalization

Author:

Jönsson Johanna1,Wang Lianqing12,Kajitani Naoko1ORCID,Schwartz Stefan1ORCID

Affiliation:

1. Department of Medical Biochemistry and Microbiology, Uppsala University , BMC-B9 , 751 23  Uppsala , Sweden

2. Center of Translational Medicine, Zibo Central Hospital , 255036  Zibo , China

Abstract

Abstract High-risk carcinogenic human papillomaviruses (HPVs), e.g. HPV16, express the E6 and E7 oncogenes from two mRNAs that are generated in a mutually exclusive manner by splicing. The HPV16 E7 mRNA, also known as the E6*I/E7 mRNA, is produced by splicing between splice sites SD226 and SA409, while E6 mRNAs retain the intron between these splice sites. We show that splicing between HPV16 splice sites SD226 and SA409 is controlled by a splicing enhancer consisting of a perfect repeat of an adenosine-rich, 11 nucleotide sequence: AAAAGCAAAGA. Two nucleotide substitutions in both 11 nucleotide sequences specifically inhibited production of the spliced E6*I/E7 mRNA. As a result, production of E7 protein was reduced and the ability of HPV16 to immortalize human primary keratinocytes was abolished. The splicing-enhancing effect was mediated by the cellular TRAP150/THRAP3 protein that also enhanced splicing of other high-risk HPV E6*I/E7 mRNAs, but had no effect on low-risk HPV mRNAs. In summary, we have identified a novel splicing enhancer in the E6 coding region that is specific for high-risk HPVs and that is critically linked to HPV16 carcinogenic properties.

Funder

Swedish Research Council

Swedish Cancer Society

Stiftelsen Clas Groschinskys Minnesfond

Publisher

Oxford University Press (OUP)

Subject

Genetics

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