Antisense Translates into Sense

T he paradigm that DNA is the central bank of genetic information within the cell, and that portions of the DNA are copied via transcription to RNA, which is subsequently decoded to synthesize protein in a cell, is basically true throughout cellular evolution. However, it is also true that although this is a general blueprint for regulating how genes are expressed, evolution, with its varied selective pressures, has allowed organisms to develop many different mechanisms for regulating gene expression. As a consequence, a plethora of novel regulatory schemes from bacteria to mammalian cells has been described. Organisms with constraints on ge-nome size have used novel genetic tricks to both regulate gene expression and synthesize multiple proteins from a single gene. However, in higher eucaryotes, the common perception is that genome size is not an issue, and that genes will typically be far apart from each other and can be regulated by independent control mechanisms. Although genes in mammalian cells are generally separated by large chunks of DNA, the paper by Van den Eynde and colleagues in this issue (1) demonstrates that this is not always the case. What started off as a project to isolate a tumor specific antigen from a renal carcinoma cell led to the discovery of a protein product that is encoded within another gene from its antisense strand (Fig. 1). The project began by isolating a clone of a CTL from a kidney cancer patient that responded to tumor cells. A cDNA library prepared with RNA from the renal tumor cells was trans-fected, along with HLA-B7 gene, into COS cells. A cDNA was isolated that was able to stimulate the CTL cells. Further analysis indicated that the transcript should be ‫ف‬ 1.4 kb in size. Surprisingly, however, the transcript migrated as a 2.2-kb mRNA on a Northern blot. This paradox was resolved when Van den Eynde and colleagues characterized additional cDNA clones from this library. Unexpectedly, these results led to the discovery that the tumor-specific an-tigen was not encoded within the open reading frame of this gene. Rather, it resided within this gene but initiated its transcription within its first intron and synthesized the RNA from the complementary (or antisense) strand of this gene (Fig. 1). The authors named the gene encoding the 2.2-kb RNA band RU2S, while the gene encoding the tumor specific antigen transcribed in the opposite direction was called RU2AS. The RU2S transcript …