Genes have stretches of (protein) coding DNA sequences interspersed with stretches of non-coding DNA sequences. The first step in making the protein is the faithful transcription of the entire gene's sequence into an RNA sequence. The RNA is then 'spliced' such that the non-coding sequences are removed and the coding sequences are assembled in a linear fashion to form the template for translation from RNA to protein.
"Until now it was thought that colinearity of DNA and protein sequences was only interrupted by RNA splicing," says LICR's Dr. Benoit Van den Eynde, the study's senior author. "This new study shows that protein splicing also occurs, and may even result in protein fragments, or peptides, being spliced together in the order opposite to that which occurs in the parental protein." According to Dr. Van den Eynde, this novel phenomenon occurs during the physiological function of 'antigen processing,' which produces antigenic peptides; the 'red flags' that mark cells for destruction by the immune system.
The immune system attacks 'foreign' cells - be they tumor cells, virally infected, or donated by another person - when T lymphocytes recognize antigenic peptides displayed on the cell surface. The antigens are created by 'proteasomes,' components of the cell machinery that cut foreign proteins into peptides that are then displayed on the cell surface for recognition and destruction by CD8+ T lymphocytes. However, the Belgium/USA team has found that proteasomes can also splice the peptide fragments together in a reverse order to that encoded by the protein's DNA sequence template. This takes the possible number of antigens from any one protein into potentially thousands of sequence configurations.
The sequence of the first human cancer-specific antigen, which was identified at the LICR Brussels Branch, has allowed the development of antigen-specific cancer vaccines that are in clinical trials around the world. This study describes a mechanism that significantly extends the number of antigenic peptides that can be produced from a single protein, and therefore widens the applicability of peptide vaccines against cancer and infectious diseases.
The Ludwig Institute for Cancer Research (LICR) is the largest international not-for-profit institute dedicated to understanding and controlling cancer. With nine Research Branches and one Centre for Clinical Sciences in seven countries, the scientific network that is LICR quite literally spans the globe. LICR has developed an impressive portfolio of reagents, knowledge, expertise, and intellectual property, and has also assembled the personnel, facilities, and practices necessary to patent, clinically evaluate, license, and thus translate, the most promising aspects of its own laboratory research into cancer therapies.