Grant: Operating Grant

When a gene is activated, it is copied ("transcribed") from DNA into a string of molecules called a messenger RNA (mRNA). The middle section of each mRNA encodes the information that is translated into the corresponding protein sequence; the two ends, called untranslated regions (UTRs), play a number of other important roles. This proposal concerns the tail end of the mRNA, known as the 3' UTR, which helps to regulate the stability and location of the mRNA and the amount of the corresponding protein that is produced. The point at which the transcription of a given mRNA ends is determined by the presence of a sequence called a polyadenylation site. Some genes have more than one such site, meaning that there can be two or more different forms of the corresponding mRNA, with different 3' UTRs and therefore different levels of activity. Changes in the ratio of the different forms are thought to contribute to the development of a range of disorders, including some cancers. The methods currently used to study polyadenylation require an extra set of experiments to be run, which is expensive and slow. However, Drs. Birol and Karsan and their teams have obtained evidence that polyadenylation can be studied alongside other important types of transcriptional regulation, using data from experiments that are already performed as part of standard analysis. They propose to develop a method to integrate polyadenylation analysis with these standard analyses, and to test the new method by characterizing how the use of different polyadenylation sites changes in a type of leukemia.