Multiple mRNA species are generated by alternate polyadenylation from the human calmodulin-I gene.

Three distinct genes encode an identical calmodulin protein in mammalian cells. In addition, multiple mRNA transcripts, with approximate sizes of 1.6 kb and 4.4 kb, are visualized on Northern blots hybridized to calmodulin-I cDNA probes. To elucidate the mechanism generating multiple calmodulin mRNAs, the complete sequence of the 4194 base human calmodulin-I mRNA was determined from cDNA clones and 3' rapid amplification of complementary ends (3' RACE). The 5' untranslated region of calmodulin-I mRNA contains a GC-rich domain containing multiple repeats of GGC interrupted by a GCA sequence, as well as a tandem repeat sequence of eight GCA triplets. The 3' untranslated region of calmodulin-I mRNA contains two canonical and one aberrant (ATTAAA) polyadenylation signal, consistent with the sizes of 1.6 kb and 4.4 kb mRNAs visualized on Northern blots, and a potential minor 4.2 kb mRNA detected by 3' RACE. Hybridization experiments using specific probes upstream and downstream of the polyadenylation signals demonstrated that alternate use of polyadenylation signals is the molecular mechanism for multiple calmodulin-I mRNA transcripts in human cells. Thirteen adenine rich elements with the motif AUUUA were detected in the 3' untranslated region. Three such motifs are embedded in regions that are conserved with the rat 3' untranslated region of calmodulin-I mRNA. One of these is surrounded by an adenine-uridine rich region that can form an 11-base pair stem structure. We propose that sequences in the 3' untranslated region of calmodulin-I mRNA may play a role in the regulation of calmodulin expression.