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RNA Splicing and Breast Cancer
In 1977, CSHL scientist Richard Roberts and his colleagues published a paper whose title began "An amazing sequence arrangement..." Rich's use of the adjective "amazing" in a serious scientific article was highly unusual and strangely prescient, because the paper reported a discovery for which he would later win the Nobel prize. A number of papers from Cold Spring Harbor Laboratory and MIT published the discovery that genes are not usually contiguous, but rather occur as blocks of relevant coding sequences (later called exons) that are interspersed with blocks of intervening, noncoding sequences (introns).
Introns are removed at the level of RNA by a splicing mechanism. This year, Adrian Krainer and his colleagues discovered why particular mutations in the BRCA1 gene alter premessenger RNA splicing and thereby predispose individuals to breast and ovarian cancer.
Although complex in detail, the basic splicing mechanism involves cutting a premessenger RNA molecule at two sites (the splice junctions), discarding the intron thus released, and joining the exons together. This basic splicing mechanism is mediated by the binding of splicing factors to the splice junctions and the action (e.g., cutting and joining) of splicing factors at these sites. Recently, however, additional sites that stimulate splicing have been identified within exons. These sequences are called exonic splicing enhancers or ESEs. Adrian and his CSHL bioinformatics colleague Michael Zhang have developed rules for predicting the presence of ESEs within genes of particular interest. They discovered that a mutation in the BRCA1 gene–known to alter splicing and predispose individuals to breast and ovarian cancer–disrupts an ESE. In addition, Adrian found that disruption of ESE function may contribute to many other diseases, including cystic fibrosis, neurofibromatosis, Wiskott-Aldrich syndrome, and Menkes disease.
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