Mechanism of Splicing of Unusual Intron in Human Proliferating Cell Nucleolor Pl2O.
Abstract
Previously we identified three classes of exonic splicing enhancer (ESE) motifs recognized by the human SR proteins SF2/ASF, SRp40 and SRp55. This year I identified functional ESEs recognized by SC35 or SRp30c. The SC35 motifs, whose consensus is GGYYCSYR, are abundant in the IgM C4 exon, which follows an intron that splices in S100 extract complemented by SC35, but not by SF2/ASF. SF2/ASF motifs occur infrequently in this exon. - In contrast, both SC35 and SF2/ASF motifs co-exist in the HIV Tat T3 exon, following an intron that splices in S100 extract plus SC35 or SF2/ASF. I investigated the relationship between SR protein consensus motifs and human mutations using computational and experimental approaches. A point mutation in exon 18 of BRCA1, which causes exon skipping and familial breast and ovarian cancer, disrupts an SF2/ASF motif. In vitro splicing showed that exon skipping results from disruption of the SF2/ASF-ESE interaction. Mutations in other human disease genes were also found to interrupt SR protein ESE motifs. Therefore, many human diseases caused by missense or nonsense exon mutations may result from splicing defects, which are often overlooked. Our approach provides a simple way to study the phenotypic basis of mutations in human disease genes.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 1998
- Accession Number
- ADA366558
Entities
People
- Hongxiang Liu
Organizations
- Cold Spring Harbor Laboratory