CHOP/GADD153 and methionyl-tRNA synthetase (MetRS) genes overlap in a conserved region that controls mRNA stability

The transcription factor CHOP is involved in the regulation of the cell div ision cycle and the control of programmed cell death in response to cellula r stress. CHOP expression has been linked with several forms of cancer. A r eciprocal translocation between the CHOP and TLS RNA-binding protein gene r esults in myxoid liposarcoma and amplifications of the CHOP gene are associ ated with solid tumors including several types of sarcomas. Here we report the mapping of the methionyl tRNA synthetase (MetRS) gene to the identical 12q13 locus where the CHOP gene had previously been mapped. PCR analysis de monstrates a tail-to-tail overlap of both genes over a 55-bp region. As a r esult the two mRNAs share a 3' UTR complementary sequence allowing an in vi vo interaction between the two mRNAs. An AU-rich regulatory element (ARE) k nown to control mRNA stability resides in the overlapping sequence. To test for functional significance of the ARE a luciferase reporter plasmid conta ining the 3'UTR of CHOP was constructed. Transfection experiments in NIH-3T 3 cells show that CHOP 3'UTR confers a significantly lower activity than a control reporter or a reporter in which the region overlapping the MetRS mR NA is deleted. The conservation of this overlapping of the CHOP and MetRS g enes and the role of their complementary sequence in the control of mRNA st ability suggest the existence of a functional link between the expression o f these two genes. (C) 1999 Academic Press.