LONG NONSTOP READING FRAMES ON THE ANTISENSE STRAND OF HEAT-SHOCK-PROTEIN-70 GENES AND PRION PROTEIN (PRP) GENES ARE CONSERVED BETWEEN SPECIES

Several mammalian genes, including heat shock protein (Hsp70) and prio n protein (PrP) genes, have been reported to have long open reading fr ames (ORFs) or non-stop reading frames (NRFs) in the antisense directi on. A simple explanation would be that these long antisense reading fr ames, which are usually in the same triplet frame as the coding strand , are the fortuitous byproduct of a high overall [G+C] content with co ncomitant preference for G/C over A/T in the third codon position, a p reference for RNY type codons (purine/any nucleotide/pyrimidine), and/ or a bias against serine and leucine, the only amino acids with codons that can be read as stop codons in the antisense direction. The PrP g enes and most heat shock genes with long antisense NRFs (aNRFs) are in deed relatively [G+C] rich but do not show a bias against serine and l eucine. In several vertebrates investigated, at least one of the Hsp70 genes has a long antisense reading frame, and we found that some, tho ugh not all, putative stop codons in long Hsp70 antisense reading fram es were due to sequencing errors. The PrP gene contains an extended an tisense open reading frame in all 45 eutherian mammals tested, but not in a marsupial and in a bird. In the PrP gene, the long, protein-codi ng exon also harbors the antisense nonstop reading frame. In both Hsp7 0 and PrP genes, the putative antisense protein sequence is well conse rved. Even though there is no clear evidence in Hsp70 or PrP genes for the existence of the respective antisense proteins, we speculate that such antisense proteins serve to regulate the genuine Hsp and PrP pro teins under special circumstances. Alternatively, regulation might occ ur at the RNA lever, and the antisense RNA would merely lack stop codo ns to prevent its rapid degradation by an mRNA quality control mechani sm that is triggered by premature stop codons. We note that both Hsp a nd PrP are involved in physiological or pathological protein aggregati on phenomena, that scrapie prions have been reported to modify the exp ression or localization of heat shock proteins, and that in yeast, pro pagation of a prion-like state (PSI+) depends on a heat shock (Hsp104) protein.