Y RNA: An Overview of Their Role as Potential Biomarkers and Molecular Targets in Human Cancers

Abstract

Y RNA are a class of small non-coding RNA that are largely conserved. Although their discovery was almost 40 years ago, their function is still under investigation. This is evident in cancer biology, where their role was first studied just a dozen years ago. Since then, only a few contributions were published, mostly scattered across different tumor types and, in some cases, also suffering from methodological limitations. Nonetheless, these sparse data may be used to make some estimations and suggest routes to better understand the role of Y RNA in cancer formation and characterization. Here we summarize the current knowledge about Y RNA in multiple types of cancer, also including a paragraph about tumors that might be included in this list in the future, if more evidence becomes available. The picture arising indicates that Y RNA might be useful in tumor characterization, also relying on non-invasive methods, such as the analysis of the content of extracellular vesicles (EV) that are retrieved from blood plasma and other bodily fluids. Due to the established role of Y RNA in DNA replication, it is possible to hypothesize their therapeutic targeting to inhibit cell proliferation in oncological patients.

Keywords: DNA replication; RNY1; RNY3; RNY4; RNY5; RO60; cancer etiology; cancer microenvironment.

Figure 1

Evolutionary conservation of Y RNA in vertebrates. The dendrogram shows the conservation of human hY1 in monkeys, dogs, rodents, and birds; only best matches (identity >95%) were selected. The tree was obtained through the NCBI BLAST website (URL: https://blast.ncbi.nlm.nih.gov/Blast.cgi, accessed on April 2020), using default settings. Out of the 100 results displayed, we selected only those coming from genome sequences, thus excluding predicted sequences, human pseudogenes, bacterial artificial chromosome (BAC) clones, and other constructs. The color codes, set by default by the NCBI website, are as follows: yellow highlight: query sequence; light blue dots: hawks and eagles; pink dots: birds; brown dots: rodents; blue dots: primates; green dots: carnivores; grey dots: nodes.

Figure 2

Structure of human Y RNA. The structure was retrieved from the literature [19,21,22], but alternative structures with minor differences have been reported as well [23,24]. The domains are the poly-U tail (yellow), the lower stem (green), the bulge (violet), the upper stem (blue), and the loop (red).

Figure 3

A schematic representation of Y RNA life cycle. The light blue area represents the nucleus (the dotted line indicates the presence of nuclear pores) and the molecular events occurring inside it; the yellow area represents the cytoplasm; the white space represents the surrounding extracellular environment. Y RNA are transcribed by POLIII and, if bound by SSB/La, may remain inside the nucleus to perform specific tasks like promoting DNA replication or other functions, upon binding to specific proteins such as those reported in Table 1. In many cases, these additional functions are not fully understood, since Y RNA binding companions are known, but not their role. If Y RNA are bound by RO60 inside the nucleus, they can be exported into the cytoplasm with the help of specific carrier proteins. Once there, Y RNA may perform several tasks, either alone or in RNP complexes. Y RNA may be stabilized through their binding to SSB, RO60, or other proteins, and they may contribute to the stabilization of several target molecules. Moreover, they may also be excreted in the extracellular environment either as free and complete RNA, or as free RNP complexes, or inside micro vesicles. Y RNA excretion may also occur after a specific cleavage, that generates the YsRNA. Once in the extracellular environment, Y RNA may be internalized by target cells to perform additional tasks.