Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 3, Pages 938-943Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.031564098
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Funding
- NCI NIH HHS [R01 CA114197-01A2, R01 CA114197] Funding Source: Medline
- NEI NIH HHS [R01 EY014576-03, R01 EY014576] Funding Source: Medline
- NIGMS NIH HHS [R01 GM070967, R01 GM070967-02] Funding Source: Medline
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We have established a model system using the caspase-2 pre-mRNA and initiated a study on the role of alternative splicing in regulation of programmed cell death. A caspase-2 minigene construct has been made that can be alternatively spliced in transfected cells and in nuclear extracts. Using this system, we have identified a 100-nt region in downstream intron 9 that inhibits the inclusion of the 61-bp alternative exon, This element (ln100) can facilitate exon skipping in the context of competing 3' or 5' splice sites, but not in single-intron splicing units. The In100 element is also active in certain heterologous pre-mRNAs, although in a highly context-dependent manner. Interestingly, we found that ln100 contains a sequence that highly resembles a bona fide 3' splice site. We provide evidence that this sequence acts as a decoy acceptor site that engages in U2 snRNP-dependent but nonproductive splicing complexes with the 5' splice site of exon 9, hence conferring competitive advantage to the exon-skipping splicing event (E8-E10), These results reveal a mechanism of action for a negative intronic regulatory element and uncover a role for U2 snRNP in the regulation of alternative splicing.
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