Characterization Of Intronic Polyadenylation Isoforms In Normal Human Cells And B Cell Malignancies
Alternative cleavage and polyadenylation (ApA) is most often viewed as the selection of alternative pA signals in the 3' UTR, generating 3' UTR isoforms that code for the same protein. However, ApA events can also occur in introns, generating either non-coding transcripts or truncated protein-coding isoforms due to the loss of C-terminal protein domains, leading to diversification of the proteome. Due to lack of a study that characterizes the intronic polyadenylation isoforms on a genome wide level, we decided to investigate the cell type specificity and potential functional consequences of isoforms generated by intronic ApA. We therefore carried out an analysis of 3'-seq and RNA-seq profiles from chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) samples as compared to mature human B cells (naïve and CD5+) and plasma cells, respectively, together with our previous 3'-seq atlas generated from a wide variety of tissues and cell lines. We found that in more than 20 percent of human genes, intronic polyadenylation (IpA) sites are used to generate alternative 3' ends. This analysis shows that IpA is a normal and regulated process, most widely used in immune cells. IpA events are enriched near the start of the transcription unit, yielding non-coding transcripts or messages with minimal coding sequence (CDS). The expression of truncated mRNAs contributes to proteome diversity in normal cells. However, we found that cancer cells can take advantage of this mechanism to mimic genetic mutations. Many genes with truncating mutations in CLL express IpA isoforms. Cancer cells lacking genetic aberrations can disrupt IpA to generate truncated mRNAs. These IpA isoforms potentially have similar functional outcome as truncating mutations. In this study we unravel a new mechanism by which cancer cells can contribute to tumorigenesis.
3'-seq; 3' UTR; chronic lymphocytic leukemia; intronic; multiple myeloma; polyadenylation
Physiology, Biophysics & Systems Biology
Doctor of Philosophy
Attribution-NonCommercial-NoDerivatives 4.0 International
dissertation or thesis
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