Common Cause: RNA Splicing and Human Disease
reast and ovarian cancer. Cystic fibrosis. Hemophilia. Muscular Dystrophy. These and many other diseases often have a common, underlying cause, according to a recent study by CSHL scientist Adrian Krainer. Adrian's lab has found that some genetic mutations leading to these very different diseases may all alter a process called "RNA splicing" in the same way.
RNA splicing is a terrifically complex, crucially important process. The study of RNA splicing has a rich past and present at CSHL, including its co-discovery here in 1977 and a corresponding Nobel Prize in 1933 [See The Rich Past & Present of RNA Splicing Research at CSHL]. What is RNA splicing, why is it important, and how has Adrian recently connected defects in RNA splicing to human disease?
Genes are made of DNA. They ultimately specify virtually everything that happens in living organisms. Surprisingly, most genes are not arranged in a simple, uninterrupted sequence from beginning to end. Instead, genes frequently contain alternating stretches of "protein-coding" and "non-coding" regions. If a gene is likened to a sentence, then instead of the gene reading, "I went to the store to buy some milk" it might read, "I went non-coding region to the store to non-coding region buy some milk."
These alternating coding and non-coding regions of a gene are transcribed into a continuous strand of RNA, a cousin of DNA. Next (here comes RNA splicing), non-coding pieces of RNA (a.k.a. "introns") are cut out of the strand, and the remaining coding pieces of RNA (a.k.a. "exons") are joined together or spliced [see figure at Common Cause]. Thus, RNA splicing creates a template for protein synthesis called messenger RNA.
During normal RNA splicing, all introns must be removed and, with some interesting exceptions, all exons must be included. If an exon is not included, it is "skipped," resulting in proteins that lack segments. For example, a protein produced from the aforementioned RNA template in which the "to the store to" exon is skipped during splicing will read, "I went to buy some milk." Such exon skipping can have serious consequences: It is precisely what happens in some forms of breast and ovarian cancer, cystic fibrosis, hemophilia, muscular dystrophy, and many other diseases.
Adrian has focused part of his lab's work on determining why particular genetic mutations cause exon skipping. One of his studies started with the breast cancer susceptibility gene BRCA1 and soon encompassed some 17 additional disease-related genes. Genetic mutations in the BRCA1 gene are responsible for approximately half of inherited breast cancer and more than 80% of inherited breast and ovarian cancer.
To generate a single, properly spliced BRCA1 messenger RNA molecule, the splicing machinery in the cell nucleus must cut the RNA in 46 places and paste some 24 exons together in the correct order. One form of heritable breast cancer has
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