IS A NEW DEAL IN THE CONTROL OF VENEREAL DISEASE NECESSARY?--1

Abstract

<h3>Abstract</h3> While near cognate codons are frequently used for translation initiation in eukaryotes, their efficiencies are usually low (&lt;10% compared to an AUG in optimal context). Here we describe a rare case of highly efficient near cognate initiation. A CUG triplet located in the 5’ leader of <i>POLG</i> mRNA initiates almost as efficiently (~60-70%) as an AUG in optimal context. This CUG directs translation of a conserved 260 triplet-long overlapping ORF, which we call <i>POLGARF</i> (<i>POLG</i>Alternative Reading Frame). Translation of a short upstream ORF 5’ of this CUG governs the ratio between DNA polymerase and POLGARF produced from a single <i>POLG</i> mRNA. Functional investigation of POLGARF points to extracellular signalling. While unprocessed POLGARF resides in the nucleoli together with its interacting partner C1QBP, serum stimulation results in rapid secretion of POLGARF C-terminal fragment. Phylogenetic analysis shows that <i>POLGARF</i> evolved ~160 million years ago due to an MIR transposition into the 5’ leader sequence of the mammalian <i>POLG</i> gene which became fixed in placental mammals. The discovery of <i>POLGARF</i> unveils a previously undescribed mechanism of <i>de novo</i> protein-coding gene evolution. <h3>Significance Statement</h3> In this study, we describe previously unknown mechanism of <i>de novo</i> protein-coding gene evolution. We show that the <i>POLG</i> gene, which encodes the catalytic subunit of mitochondrial DNA polymerase, is in fact a dual coding gene. Ribosome profiling, phylogenetic conservation, and reporter construct analyses all demonstrate that <i>POLG</i> mRNA possesses a conserved CUG codon which serves as a start of translation for an exceptionally long overlapping open reading frame (260 codons in human) present in all placental mammals. We called the protein encoded in this alternative reading frame POLGARF. We provide evidence that the evolution of <i>POLGARF</i> was incepted upon insertion of an MIR transposable element of the SINE family.