Pseudogenes act as “decoys” for microRNAs

MicroRNAs are known to regulate gene expression by interacting with incompletely complementary sequences in a target messenger RNA. But is the converse true: can mRNA expression affect the distribution of miRNAs? A new study¹ shows that the 3′ untranslated region of a pseudogene — the tumour suppressor pseudogene PTENP1 — can bind the same miRNAs as the related protein-coding gene, PTEN. This suggests that pseudogenes may have a biological function as ‘decoys’, sequestering miRNAs and thereby affecting their regulation of expressed genes.

The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory role that relies on their ability to compete for microRNA binding, independently of their protein-coding function. As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1 locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active. These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs. (Read more… )

1. Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi, PP. (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033-38. [abstract]