Comparative genomic analysis of the 3' UTR of human MDM2 identifies multiple transposable elements, an RLP24 pseudogene and a cluster of novel repeat sequences that arose during primate evolution.

Abstract

The MDM2 oncogene is a negative regulator of the p53 tumour suppressor. This relationship appears to have originated over a billion years ago. The human MDM2 gene encodes a variety of mRNAs with exceptionally long 3'UTRs (up to 5.7kb); however, it was unclear whether MDM2 3'UTRs from other species are similarly long or conserved at the sequence level. Here, we report that all but one of the primate species most closely related to humans (greater and lesser apes) have similarly long 3'UTRs with high sequence similarity across their entire length. More distantly related species (Old world monkeys and new world monkeys) tend to have shorter MDM2 3'UTRs homologous to the corresponding position of the human MDM2 3'UTR while non-primate species exhibit little similarity at all. Remarkably, DNA sequences downstream of the shorter primate 3'UTRs are syntenic with distal regions in the human and other ape MDM2 3'UTRs. These homologous non-transcribed intergenic and transcribed 3'UTR-encoding regions are comprised of a variety of transposable elements, an RLP24 pseudogene and a cluster of novel repeat sequences suggestive of another unknown transposable element. Our analysis suggests that the primary difference between long and short MDM2 3'UTRs is a switch in polyA site usage to include conserved transposable elements that remain intergenic in more distantly related primates. It will be important to determine the relative contribution of these elements to post-transcriptional and translational regulation of MDM2 and hence p53-mediated tumour suppression.