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Correspondence to Author: Witold Światowy, 

Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, Poland.

Abstract:   Numerous research have been conducted on RNAbased compounds, revealing new architectures and functionalities that these molecules are capable of. Thanks to next-generation sequencing, very small RNAs have been observed recently, and the number of newly identified RNA molecules is growing quickly. In addition to Observed short oligonucleotides with structures derived from tRNA and snoRNA molecules were found not to be progenitors of known RNA molecules. Researchers have been interested in these structures because of the comparatively high level of tRNA or snoRNA fragment accumulation. Moreover, some parent molecule components were missing. Moreover, the roles of derivatives of well-known RNA molecules differ from those of their parent molecules. Like miRNA, their primary function is to control the expression of genetic information. Furthermore, several of the miRNAs that have been reported are tRNA or snoRNA derivatives. In the lack of a description of the macroeffects that these recently identified compounds impose, the majority of research on them is focused on their detection and analysis. molecular mechanism that gives rise to and drives them.

Keywords:   Noncoding RNA,tRNA,snoRNA,RNA processing,sdRNA,tRF

Introduction: Among the most significant chemical groups found in living things are RNA molecules. Initially, it was believed that they only served as an intermediary product in the process of translating genetic information from DNA into proteins. Prior to the identification of ribosomal RNA (rRNA) and transfer RNA (tRNA), which demonstrated that RNA can serve additional purposes in cells [1], non-coding RNA was assumed to be non-functional and worthless. More investigation improved our knowledge of RNA [2]. Next, RNA was separated into two categories: non-coding (ncRNA) and coding (mRNA). At first, RNAs without an open reading frame (ORF) and with a seven-nucleotide cap were categorized as non-coding RNAs (ncRNA). This perspective has evolved, and all RNAs that do not encode proteins are now classified as ncRNAs. [3]. There are two categories of non-coding RNA (ncRNA): interference RNA and housekeeping RNA. Housekeeping RNA is made up of components including rRNA, tRNA, and others whose expression is essential to a cell’s ability to operate normally. Transfermessenger RNA (tmRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), and a few others. Posttranscriptional gene silencing is the function of microRNA (miRNA), which is categorized as interference RNA [3]. The nomenclature for RNAs may need to be revised in the future years as information regarding ever-newer RNAs becomes available. Terms like long non-coding RNA, short RNA, and microRNA may no longer be appropriate. This needs to be taken into account along with the titles that the RNA is namely, abnormally tiny RNA, as reported in this paper. The tRNA and snoRNA fragments are the molecules from this RNA category that are most commonly reported. The transfer RNA is in charge of supplying the ribosomes with amino acids. They transfer free amino acids to translation sites by binding to them in a particular way. Apart from their primary role of delivering amino acids to ribosomes, they can also be a retrovirus primer, transfer amino acids to other metabolic pathways, and control cell death by cytochrome binding [4]. Because all tRNA molecules must be able to interact with the rRNA in a comparable way, all tRNAs have the shape of a four-leaf clover. rRNA is capable of differentiating D loops in addition to the anticodon loop. T-loops (Fig. 1) as well. These are significant components when considering the molecules that will be covered later. Given the great degree of evolutionarily conserved nature of transporting RNAs, it is possible that molecules generated during the process of their breakdown were among the earliest regulatory elements to arise [5]. An equivalent term for small nucleolar RNA is small nuclear RNA (snRNA), which highlights the precise location of these molecules. Their length ranges from 60 to 300 nucleotides, and they are primarily found in the nucleolus but are also seen in Cajal bodies. This particular RNA type is present in both eukaryotes and archaea, which is why they most likely evolved two to three billion years ago. Introns are where snoRNA is most frequently coded in humans. Introns are typically degraded upon mRNA splicing, but snoRNAs are able to circumvent this destiny by building complexes with proteins that we refer to as snoRNPs [5]. The tiny nucleolar RNA is classified into two categories based on structural and functional differences. RNA can have nucleotides chemically modified by C/D and H/ACA snoRNPs. This occurs primarily in ribosomal RNA in translation-related regions like the peptidyl transferase center or mRNA decoding center, but it can also occur in other RNAs like snRNA in eukaryotes, tRNA in archaebacteria, and potentially brain-specific RNA. Mammals’ mRNA (Fig. 2). A suitable alteration of snRNA by soRNA molecules is required for the correct operation of spliceosomes [5]. The C/D family has the ability to methylate 2′-O-ribose because fibrillarin methyltransferase is present. The H/ACE family, on the other hand, is linked to pseudouridine synthetase. A specific nucleotide can be modified via the selective hybridization of snoRNA segments with the appropriate RNA fragment [5]. More than 200 distinct snoRNA molecules exist, but not all of them have been linked to particular target tRNA or snRNA molecules. These are known as orphan snoRNAs, and their roles in the body are yet unknown.

RNA DEGRADATION:   For the cell to remain in a condition of equilibrium, the degradation process is crucial. Cells possess the ability to regulate all levels and reactions. of the proteins. The processes of RNA degradation include the elimination of unnecessary normal RNA, RNA maturation (the processing of precursor molecules), quality control (the removal of particles that have been incorrectly folded or synthesized), post-transcriptional control of gene expression, and defense against non-native RNA (Fig. 3) [6,7]. The deterioration process is a vast and intricate system that still needs to be fully understood. The cleavage reaction is caused by the ribonucleases, which are classified into three classes based on where the phosphodiester bond hydrolysis occurs. The breaking of bonds within the RNA molecule is catalyzed by endoribonuclease, the detachment of a single nucleotide from the 5′ end is catalyzed by 5′-3′ exoribonuclease, and the analogue function is provided on the 3′ end by 3′- 5′ exoribonuclease. Within every subcategory, Enzyme families that recognize different substrates are numerous. While certain enzymes are highly specialized, others can be applied to target sequences that are more degenerate [7, 8]. This variety of ribonucleases demonstrates the significance of this process for the correct operation of the degrading system and is expected to provide the maximum level of reliability.organism and cell [9]. An estimated 60+ distinct RNA-degrading enzymes from multiple families have been identified in humans.[7]. The majority of the mechanisms of degradation that have been studied and explained relate to activities that take place in prokaryotic cells. Mammalian processes are less well characterized than yeast processes among the eukaryotes. Nonetheless, there is a theory that Saccharomyces cerevisiae and mammalian mechanisms are comparable. [8]. The policy plan RNA molecules are made up of two parts: their source and their destination. For cells to operate properly, the presence of RNA molecules must be dynamically controlled. This is because, in addition to synthesising new RNAs, a procedure must be in place to monitor the quality of newly produced particles and degrade them as necessary. This is significant because homeostasis may be upset if a particular mRNA exists for an extended period of time [8]. The two stages of the degradation process are as follows: the first is the identification of a defective particle, which varies greatly amongst organisms. The chosen molecule’s breakdown forms the basis of the second stage. This is the same for nearly all ribonucleases. Although the exact mechanism for identifying molecules with nucleus defects is unknown, it is hypothesized that these molecules cannot proceed rapidly enough to the next phase, whereupon they are picked up by the Trf-Air-Mtr4 polyadenylation complex (TRAMP complex) and designated with a poly tail (A) before being sent down the degradation path. We now have a better understanding of the cytoplasmic breakdown mechanism. The identification of the faulty protein involves various protein components. structure that acknowledges particular drawbacks. The primary cause of degradation in the cytoplasm is the exosome complex, which is comprised of both exonuclease actions [10]. Degradation of no longerneeded mRNA occurs in the cytoplasm. This is accomplished by regulating the transcript’s longevity through the use of a poly tail at the 3′ end and a cap at the 5′ end. The poly (A) tail is 50–250 base pairs long and is bound by various protein components that guarantee the structure’s stability. Poly (A)-specific ribonuclease 3′-5′ PRN exonucleases shorten the tail, and the tail is destined for destruction when it reaches a length of 20–25 nt at the 3′ end. Compared to mRNAs, other RNAs are more stable.such as rRNA and tRNA, but they also occasionally need to be broken down, as in the case of cellular shortages of essential building blocks, rRNA ribophagy, or the dispersion of entire ribosomes.

STABLE BYPRODUCTS OF DEGRADATION:   Scientists are seeing ever-tinier structures because of a constantly evolving study technique, mostly because of extremely efficient sequencing. Among other things, they have started to show interest in previously unconsidered very tiny structures of ribonucleic acids, on the order of a dozen or so nucleotides [11]. These short amino acids were first believed to be a temporary byproduct of the breakdown of tRNA, rRNA, or other RNA molecules with well-known and characterized activities. It was believed that these pieces had no biological use until the structure was thoroughly studied. Although the initial research indicates that The discovery that RNA molecules do not break down into single nucleotides was made in 1971. The first indication that functional RNA fragments exist was made in 2008 when researchers discovered that snoRNA fragments functioned similarly to miRNA [5]. It was discovered that severing tRNA stopped the synthesis of viral proteins, acting as a defense against phage T4 [12]. Studies on different particles with structures derived from tRNA, snoRNA, rRNA, or, to a lesser extent, other molecules, have been conducted [5,13,14]. Numerous creatures from all branches of the biological tree have been found to contain particles produced from functional RNAs. tree of life’s evolutionary relationships [15]. They have been discovered in eukaryotes, which includes plants [19], prokaryotes [18], and archaea [16, 17]. Of course, mammals [20, 21]. The fact that the compounds under discussion are so widely distributed implies that they originated early on and were probably one of the main mechanisms regulating gene expression [17]. Scholars who have explored their functioning and described their possibilities have given them different names. They were written as tRF (tRNA-derived RNA fragments), usRNA (unusually small RNA), hcnRNA (high copy number RNA), sitRNA (stress-induced tRNA-derived RNA), or tRNA halves, used interchangeably with tsRNA (tRNA-derived small RNA) due to the lack of a unified nomenclature for RNA fragments derived from known RNA structures [11,13,20,22– 24]. As miRNA, several fragments have been categorized [1,25].

THE PATHOPHYSIOLOGY AND ROLES OF CUT SNORNA FRAGMENTS:   snoRNA fragments are the second most spoken about class of deteriorators. Protozoa [36], viruses [48], and mammals [27], including humans [27,49], have all been shown to exhibit them. Although there have been instances of alternative nomenclature, such as psnoRNA (processing snoRNA) or sno-miRNA (pointing to functional similarity with miRNA), they are typically referred to in the nomenclature as sdRNA (sno-derived RNAs) [50,51]. The naming issue with snoRNA degradants is different from that of derived tRNA, though, as there is no differentiation between those derived from the C/D box and those derived from the H/ACA box. There may not be much exact information available regarding these compounds because some research have not taken these differences into consideration; For instance, the results of a general test for sdRNA particle length range from 18 to 22 nt [48]. Research outlining the origin and length of the short RNAs examined in people provide significantly more accurate data, however it frequently contains contradictions. While molecules from the second group often have lengths of 17–22 nt and occasionally exceed 27 nt, degradants produced from H / ACA typically have lengths of 20–24 nt [27,35,49]. Studies started use deep sequencing to look into small-sized RNA in the wake of small non-coding RNAs derived from snoRNA [47]. It has been shown that short RNAs formed from socalled tiny RNAs (snoRNA) can bind proteins belonging to the Argonaute family and subsequently inhibit the expression of certain genes [27, 52]. sdRNAs got started attributable in part to sdRNA that is formed from soRNA ACA45, to be compared to miRNA. Similar to how the tested sdRNA’s precursor Pre-miRNA forms a hairpin structure and is subsequently processed by Drosha-independent Dicer. Additionally, the ACA45-derived sdRNA was shown to recognize mRNA’s 3′UTR regions in the same study. Having the capacity to bind to the Ago1 and Ago2 proteins, thereby post-transcriptionally silencing the expression of the CDC2L6 gene. Since the CDC2L6 gene product is a part of the Mediator Complex, which regulates transcription, the silence of this gene is crucial for the general transcription of genes in mammals [52, 53]. Dicer and Drosha, two enzymes involved in the synthesis of miRNA, are necessary for the formation of sdRNA, according to a different study. The research discovered a lower concentration.global sdRNA in the sample that had lower levels of Drosha and Dicer nuclease expression than the control groups [27]. This work shows that Drosha is necessary for the synthesis of at least some sdRNA. Variations in the degree of expression of some sdRNAs, like tRF or tsRNA, are typical in cancer. Prostate cancer has been linked to elevated levels of SNORD78, while NSCLC has been linked to elevated levels of SNRA42, SNORD33, SNORD66, and SNORD76, among several other factors [54]. The researchers’ observation that sdRNA can bind to AGO proteins in these instances suggests that the proteins may play a role in translation inhibition. These investigations, however, could not clarify the molecular processes underlying these dependencies. In the document outlining Given the elevated expression of sdRNA-93 in breast cancer, it has been observed that the regulation of expression mechanism bears similarities to microRNA. Furthermore, the signal The mechanism influencing sdRNA has been identified. sdRNA-93 influences the metabolism of sarcosine by means of the pipox gene’s identification of its 3′UTR. Sarcosine metabolism is affected by the pipox gene. Nonetheless, the molecular subtypes of breast cancer are influenced by the expression level of sarcosine [55]. The sno-mir-28 molecule, which is derived from the snoRNA molecule SNORD28, is an intriguing target of sdRNA. In breast cancer cells, there is increased expression of both SNORD28 and sno-mir-28. Furthermore, SNORD HOST GEN 1 protein (SNHG1) was found to be substantially increased. The degradant molecule interferes with the p53 protein’s ability to function. A mutation in the gene producing the p53 protein, TP53, has been found to affect more than half of all genes. This protein regulates the expression of a very large number of genes. Sno-mir-28 acknowledges the 3′UTR region of TAF9B and suppresses its expression by forming a complex with the AGO protein. As a component of transcription factor IID (TFIID), the TAF9B protein stabilizes and co-activates the p53 protein. Together with sno-mir-28, TAF9B, and SNHG1, the p53 protein molecule creates a regulatory loop that modifies p53 stability and downregulates p53-dependent pathways. One of the important regulatory molecules in the development of cancer may be the tested degradant, and it may also have an noteworthy oncogene in these illnesses [56]. Because of these parallels between sdRNA and miRNA, known and described miRNAs have been screened in miRBase to see whether or not their snoRNA molecules are the precursors. Pre-miRNAs derived from H/ACA snoRNA, such HBII-99b and SNORD126 [51], as well as molecules derived from C/D snoRNA, like miR-1291/ACA34, miR-1248/ HBI-6, and miR-664/ACA36b [57], have been identified at least in part. Stable evolutionary structures are suggested by the widespread presence of sdRNA in a wide range of taxa, including those that represent primitive organisms like Giardia lamblia [36]. Researchers Scott et al. examined the similarities and differences between miRNA, sdRNA, and noRNA while highlighting the chromosomal similarities that have been preserved over time. They propose that there may have been a common ancestor for miRNA and snoRNA.either that miRNAs are descended from snoRNA [57]. It’s important to note that most derived C/D box snoRNAs preserve the parent molecule’s functional components. Frequently, they have a C box within, with the D cassettes on either side [51].

Viewpoint:   Research on molecules that can be added to the Degradome pool is still necessary in a significant way. In actuality, every field needs to explain or define this technique. How these molecules are created is the first crucial question. Numerous theories and instances of their development exist. They cannot, however, be applied to every molecule in this pool because they are not entirely described by the molecular account. Environments that favor the development of degradants are also a contentious topic; some writers have discovered that they only appear in stressful situations, while others have stated that they are additionally prevalent in physiological settings. Clarifying the process by which specific molecules develop can aid in the explanation of other fascinating questions regarding these molecules, most notably their function. A handful of their roles have already been outlined, but the narrative is yet incomplete. It has previously been shown that while not all of the particles have a miRNA-like function, some do. There are several functions that are not well explained, and this understanding might be expanded. It is important to pay attention to the evolutionary origin of the described particles, which is still unknown. The RNA molecules’ state of being discovered in numerous evolutionary tree branches suggests that they originated as regulatory molecules very early on. Unanswered concerns include whether further regulatory RNAs have developed from tRNA and small RNA.

Citation:

Witold Światowy. Entrants into the degradome pool: tRNA and snoRNA-derived molecules. Journal of Biomedicines 2024.