A novel signature for identification of upstream alternative translation initiation sites

Alternative translation initiation sites (aTIS) and the factors that determine an ideal mode of translation of mRNA in the eukaryotic system has been widely studied over the past several decades. Such studies demonstrate that single mRNA can yield multiple protein isoforms using the AUG and non-AUG start codons. While the conspicuous scanning model explains how the process of translation initiation begins when the pre-initiation complex encounters a start codon with optimal sequence context, referred to as “Kozak” consensus and the leaky scanning model explains the process of alternative translation downstream. Additionally, there are alternative translation initiation sites upstream and in-frame to the canonical AUG start site, which are present in the 5´ UTR of the mRNA. This choice of aTIS results in a longer N-terminally expanded protein isoform. It is unclear as to what are the factors that determine the selection of a start codon to be a potential upstream aTIS. In this study we investigate if there exists a third element, besides the sequence context at a certain distance from canonical AUG start codon, in the 5´ UTR of human mRNAs called the “complementary matching palindrome” that differentiates an upstream aTIS from any other codon. Our results show the presence of longest complementary matching palindrome around CUG codon, which may serve as an aTIS to translate proteins that are longer than their canonical isoforms.