1993 Nobel Prize in Physiology or Medicine
Reason for Award
for the discovery of split genes
Laureates
United Kingdom of Great Britain and Northern Ireland
United States of America
Explanation
Our body’s blueprint is stored in DNA, but the blueprint is not one long sentence; there are parts that must be skipped when the cell reads it. Mr. Roberts and Mr. Sharp discovered these skip-parts, called introns. The useful parts, called exons, are stitched together to make messenger RNA. It is like making a picture book by picking only the pages you need and binding them into one book. This finding is very important for understanding how living things build complex bodies.
Related Keywords
intron
Introns are non-coding segments inserted within eukaryotic genes. They are removed from the primary transcript and are absent from mature mRNA. Their number and length vary widely per gene and constitute most of the transcribed length in humans. Introns can contain functional elements such as transcriptional enhancers and templates for microRNAs. Their presence facilitates exon reorganization and is thought to drive evolutionary diversity.
exon
Exons are sequences that remain in mature mRNA and determine the amino-acid sequence of proteins. After intron removal during splicing, exons join to form a continuous open reading frame. They are typically 50–300 nucleotides long and often correspond to functional protein domains. Exon boundaries feature GU-AG rules and branch-point motifs that guide spliceosome recognition. Some exons are selectively skipped, contributing to protein isoform diversity.
RNA splicing
RNA splicing removes introns from pre-mRNA and joins exons. A large ribonucleoprotein machine, the spliceosome, orchestrates the process with several snRNPs and accessory factors. A 2'-5' phosphodiester bond at the branch-point adenosine forms a lariat, followed by a 3'-5' exon ligation. The reaction requires ATP and involves dynamic rearrangements. Faulty splicing underlies many genetic diseases and cancers.
spliceosome
The spliceosome is a multi-megadalton complex composed of U1, U2, U4/U6, and U5 snRNPs plus numerous proteins. It cycles through several intermediates during assembly, catalysis, and disassembly, driven by ATP-dependent remodelers. Cryo-EM has provided atomic-level details of RNA-RNA and RNA-protein interactions. Many regulatory factors bind the human spliceosome, conferring tissue-specific splicing patterns. Spliceosome inhibitors are being explored as anticancer therapeutics, highlighting its drug-target potential.
alternative splicing
Alternative splicing generates multiple mRNA variants from the same gene. Modes include exon skipping, intron retention, and mutually exclusive exons; over 90% of human genes use it. This mechanism yields large protein diversity from a limited gene count. It forms a crucial regulatory layer in processes such as neuronal differentiation and immune responses. Aberrant alternative splicing causes cancer and congenital diseases and serves as a diagnostic marker and therapeutic target.
exon shuffling
Exon shuffling is an evolutionary process in which exons are rearranged, creating new protein domain architectures. Homologous recombination within introns underlies the mechanism, accelerating modular protein evolution. Signatures of exon shuffling are evident in immunoglobulins and multi-domain enzymes. Molecular analyses suggest that intron phase compatibility greatly facilitates successful shuffling. The concept is applied in protein engineering to recombine functional domains at will.
splicing-related diseases
Mutations at splice sites or dysfunction of spliceosome factors lead to many diseases. Examples include spinal muscular atrophy from faulty SMN1 splicing and myelodysplastic syndrome linked to SF3B1 mutations. Cancer cells reprogram splicing patterns to produce tumor-specific isoforms. Clinically, therapies that correct splicing using antisense oligonucleotides or small molecules are advancing. RNA-seq detection of aberrant splicing also aids diagnosis and prognosis.