Talk abstracts
Talk on Friday 04:30-04:45pm submitted by Ritam Neupane
Translation of human papillomavirus E6 protein from mRNAs with extremely short 5′-UTRs
Ritam Neupane (Department of Biological Chemistry, University of Michigan), Wenzhao Dong (Department of Biological Chemistry, Life Sciences Institute, University of Michigan), Andrew Shurer (Department of Biological Chemistry, University of Michigan), Jay B. Querido (Department of Biological Chemistry, Life Sciences Institute, University of Michigan), Rachel O. Niederer (Department of Biological Chemistry, University of Michigan)
Abstract:
Human Papillomaviruses (HPVs) are responsible for almost 5% of all cancers worldwide. They cause nearly all cervical cancer cases and are estimated to cause the deaths of 342,000 people every year. It was recently shown that a high-risk strain of HPV (HPV-18) uses mRNA with extremely short (≤5 nt) 5′-untranslated regions (5′-UTRs) to make the oncogenic protein E61. While the 5′-cap and the translation initiation proteins eIF4E and eIF4AI were shown to be involved in translation of the E6 mRNA, no known pathway of translation initiation can explain how ribosomes initiate on mRNAs with such extremely short 5′- UTRs. Using a series of biochemical, high throughput, and structural tools, we investigate the mechanism behind this pathway. Our data suggests involvement of an RNA helicase (DDX5) and a potential role of the poly (A) tail of the mRNA in the translation of mRNAs with extremely short 5’-UTRs. We have observed that translation of reporter mRNAs is stimulated by a poly (A) tail even when a cap is lacking. Increasing the length of the poly (A) tail decreases translation from reporter mRNAs. Our lab uses Direct Assessment of Ribosome Targeting (DART) to precisely identify and characterize 5′-UTR elements responsible for translational regulation. A DART assay to study thousands of systematic mutations to functionally characterize sequence and structural elements involved in translation of mRNAs with such extremely short 5′-UTRs is underway. Insights form our work will potentially illuminate a previously undescribed pathway of translation initiation used by viruses.
References:
1.García, A. et al. High-risk human papillomavirus-18 uses an mrna sequence to synthesize oncoprotein E6 in tumors. Proceedings of the National Academy of Sciences 118, (2021).
Keywords: translation initiation, HPV, DART