MiRNAs are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level. These guide RNAs direct the RNA-induced silencing complex (RISC) to complementary mRNAs that are targets for RISC-mediated gene silencing. Binding of RISC to a partially complementary mRNA results in silencing through inhibition of translation. Subsequently, both Dicer and the Argonaute protein family were discovered to have expanded roles in gene regulation including their relocalization to the nucleus where they participate in transcription, alternative splicing and even DNA repair.
To date, although many data have highlighted the role played by miRNAs in controlling gene expression, the mechanisms regulating RISC protein components expression are largely unknown. Recently, we observed a modified expression of Ago2 mRNA and protein in both WI38 fibroblasts and MCF-7 committed to senescence. Specifically, in senescent cells we obtained decreased levels of Ago2 mRNA compared to the young biological sample. In contrast, the same biological samples showed unchanged levels of the Ago2 protein. Moreover, the altered Ago2 expression was accompanied to its cellular redistribution with an enrichment to the nucleus. Overall, this first set of results leads us to investigate the molecular mechanisms controlling the expression and the post-translational modifications of Ago2 inducing the cellular relocalization of the protein in cells committed to senescence.
Cellular senescence is a particular type of cell cycle arrest involved in multiple physiological and pathological processes, including embryonic development, wound healing, tumor suppression, and organism aging (He & Sharpless, 2017). More importantly, recent studies have indicated that cellular senescence plays a causal role in aging¿related diseases, including atherosclerosis, cardiovascular dysfunction, diabetes mellitus type 2, and Alzheimer's disease (Tchkonia et al., 2010), while clearing senescent cells can delay or even reverse the aging processes in vitro and in vivo (Childs et al., 2017).
To date, alteration in the Ago2 gene expression (both up and down-regulation) has not been described across senescent cells. However, to date increased data suggest a role carried out by components of RISC complex in the expression control of hallmark genes of senescence. In this scenario, we could envisage that unravel the mechanisms controlling expression and activity of Ago2 during senescence will contribute not only to our understanding of natural cellular processes, but also offer new possibilities for the development of novel therapeutic targets and biomarkers in a wide range of pathologies.