Nucleic Acids Research, 1990, Vol. 18, No. 18 5365-5373
© 1990
MOLECULAR BIOLOGY |
Uridine branch acceptor is a cis-acting element involved in regulation of the alternative processing of calcitonin/CGRP-I pre-mRNA
Institute of Molecular Biology and Medical Biotechnology, and Laboratory for Physiological Chemistry, University of Utrecht Padualaan 8, 3584 CH, Utrecht, The Netherlands
*To whom correspondence should be addressed
Received July 17, 1990. Revised August 20, 1990. Accepted August 20, 1990.
The human calcitonin/CGRP-l (CALC-I) gene contains 6 exons and encodes two polypeptide precursors. In thyroid C-cells, calcitonin (CT) mRNA is produced by splicing of exons 1-2-3 to exon 4 (CT-encoding) and polyadenylation at exon 4. CGRP-I mRNA is produced in particular neural cells by splicing of exons 1-2-3 to exon 5 (CGRP-k-encoding) and the polyadenylated exon 6. We previously reported that model precursor RNAs containing the exon 3 to exon 5 region of the CALC-I gene are processed predominantly into CGRP-I mRNA in vitro, in nuclear extracts of several cell types (neural and non-neural). Using truncated precursor RNAs containing only the exon 3 to exon 4 region of the CALC-I gene it was shown that CT splicing is an inefficient reaction in which a uridine residue serves as the major site of lariat formation. Here we report that the low CT splicing efficiency and the dominance of CGRP-I splicing over CT splicing in vitroare primarily due to the usage of the CT-specific uridine branch acceptor. Mutation of this uridine residue into an adenosine residue resulted in a strong increase in CT splicing efficiency causing a reversal of the splicing pattern. In addition, it was shown that this point mutation also increased CT splicing efficiency in vivo. These results and data obtained from other experiments involving mutation of the CT splice acceptor site suggest that the uridine branch acceptor is a cis-acting element involved in regulation of the alternative processing of the CALC-I pre-mRNA.
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