tRNA cleavage: a new insight

Abstract

Over the past decades, tRNA was found to be a rich hub of RNA modifications such as 1-methyladenosine and 5-methycytosine modifications and others, holding more than half of all modifications occurring in RNA molecules. Moreover, tRNA was discovered to be a source of various small noncoding RNA species, such as the stress induced angiogenin cleaved tRNA halves (tiRNA) or the miRNA like tRNA derived fragments. tRNA cleavage under stress was fist discovered in bacteria and later was found to be conserved across different species, including mammals. Under cellular stress conditions, tRNA undergoes conformational changes and angiogenin cleaves it into 3' and 5' halves. 5'tiRNA halves were shown to repress protein translations. tRNA cleavage is thought of to be a cytoprotective mechanism by which cells evade apoptosis, however some data hints to the opposite; that tiRNA are cytotoxic or at least related to apoptosis initiation. tRNA cleavage also was shown to be affected by tRNA modifications via different enzymes in the cytosol and mitochondria. In this review, we will highlight the biology of tRNA cleavage, show the evidence of it being cytoprotective or a marker of cell death and shed a light on its role in disease models and human diseases as well as possible future directions in this field of RNA research.

Keywords: RNA modification; angiogenin; apoptosis; cell stress; stress granules; stroke; tRNA; tRNA cleavage; tiRNA; translation repression.

Figure 1

A schematic simplified summary of the effects of tRNA and tiRNA on cell survival under stress. Under stress condition tRNA can be retrogradely transported to the nucleus to suppress translation. tRNA itself can retard apoptosis by binding with cytochrome C. Under cellular stress conditions, Angiogenin cleaves tRNA leading to 3′ and 5′tiRNA fragments formation. So far only 5′tiRNA fragments were shown to have biological function. 5′tiRNA fragments can bind to cytochrome C, retarding apoptosis. 5′tiRNA fragments also induce translational repression, leading to cellular protection. Accumulation of certain 5′tiRNA fragments can also be cytotoxic, indicating an underlying complex regulatory mechanism that is not fully explored yet.