A Novel Function for the rTS gene

Abstract

The rTS gene codes for a naturally occurring antisense RNA to thymidylate synthase (TS) mRNA and two proteins (rTSa and rTSβ). The role of the major protein product of rTS, rTβ has been linked to alterations in TS protein expression, but the precise function of rTSβ is unknown. In this report we demonstrate that increased expression of rTSβ is associated with the decrease in TS protein expression due to production of novel, diffusible signal molecules. These signal molecules are produced more abundantly when rTSβ amounts are elevated. This hypothesis is supported by the demonstration that the rTSβ-overproducing cell line H630-1 can down-regulate TS protein in other cells without direct cellular contact. These cells are shown to secrete significant amounts of lipophilic metabolites derived from methionine, in contrast to cells that do not overproduce rTSβ. In support of the hypothesis that rTSβ is essential for the generation of these compounds, we demonstrate that rTSβ can catalyze the transfer of the carboxyl carbon of methionine from S-adenosylmethionine to a lipophilic acceptor molecule in vitro. We propose rTS is involved in regulation of TS through a novel methionine-based signaling pathway.