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Nucleic Acids Research 2005 33(3):1010-1020; doi:10.1093/nar/gki245
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Published online 17 February 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
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Article

The relationship between the prothrombin upstream sequence element and the G20210A polymorphism: the influence of a competitive environment for mRNA 3'-end formation

Mythily Sachchithananthan, Stan J. Stasinopoulos, Jeffrey Wilusz1 and Robert L. Medcalf*

Monash University, Department of Medicine, Australian Centre for Blood Diseases 6th Floor, Burnet Building, AMREP, Commercial Road Prahran, Victoria 3181, Australia 1 Department of Microbiology, Immunology and Pathology, Colorado State University Fort Collins, CO 80523 USA

*To whom correspondence should be addressed. Tel: +61 3 9903 0133; Fax: +61 3 9903 0228; Email: Robert.Medcalf{at}med.monash.edu.au

Received October 4, 2004. Revised December 27, 2004. Accepted January 24, 2005.

The human prothrombin G20210A polymorphism located at the 3' cleavage site of the mRNA results in elevated plasma prothrombin levels and increased risk of venous thrombosis. This polymorphism has been shown to directly influence a variety of processes related to prothrombin mRNA metabolism. We have constructed plasmids that express the full-length prothrombin mRNA that is polyadenylated at its natural site. The A allele prothrombin variant was more efficient than the G allele at promoting cleavage at this site in the presence of a competing poly (A) sequence. In the absence of competition, both allelic variants give rise to a similar level of cleavage site heterogeneity. An upstream sequence element (USE) was also identified within the prothrombin 3'-UTR. When placed upstream of two competing poly (A) sites, the USE directed cleavage preferentially to the proximal poly (A) site. In the absence of competition, the USE had no effect on cleavage site selection. This study suggests that the basis for the increase in prothrombin expression in A allele carriers is not due to allelic changes in cleavage site selection per se. In addition, the functionality of USEs needs to be considered within the context of endogenous sequence architecture.


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