Genetic dangers in poly(A) signals

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Abstract
The level of expression achieved by a gene is often simply associated with how efficiently it is transcribed. However, other factors can also have dramatic effects on gene expression levels. A mutant version of the human prothrombin gene that shows over‐expression of its protein product through activation of its poly(A) signal has recently been studied by Gehring et al . (2001). This apparently perturbs the delicate balance of the clotting cascade and may cause serious problems of thrombosis in affected individuals. Producing a mature, translatable messenger (m)RNA from a mammalian gene requires an amazingly complex series of molecular tricks. First, the gene must be exposed from its hidden state in chromatin (Workman and Kingston, 1998). Then, RNA polymerase II (Pol II) must be seduced by multiple activation domains of transcription factors bound and lined up on the gene's promoter or enhancers to land on the transcription start site (Blackwood and Kadonaga, 1998). This of course occurs in conjunction with numerous other proteins (general transcription factors), so that the final initiation complex is in the mDa size range (Orphanides et al ., 1996). The effectiveness of any one of these transcription initiation steps can directly determine not only the specificity, but also the level of gene expression. Complex rearrangements then occur to allow the polymerase to escape from the promoter and begin elongating through the gene (McKnight, 1996). However, with potential gene sizes of over a million nucleotides, the elongation process can be a marathon experience both in time (some 16 h) and in terms of RNA processing. Extensive intron splicing, both constitutive and alternative, occurs co‐transcriptionally (Lopez, 1998 …