A lot has been discovered in the world of molecular biology especially revelations of the RNA world. Non-coding RNAs form a major part of it. A lot more of the human genome is transcribed than as initially thought and regulation is one of the major processes the non-coding RNAs (which though transcribed do not end up producing proteins) perform. These regulatory RNAs can be small like miRNAs, siRNAs, snRNAs of the spliceosome, snoRNAs for large RNA processing etc. or they can be long as in the case of long non-coding RNAs (lncRNAs)1. Given their role in regulation these molecules play an important role in cellular biology and are therefore found critically involved in human diseases.
Introduction
The past few decades in Molecular Biology
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faecalis plasmid pAD1 par addiction module where the formation of a stem loop in the 5’ end of it’s RNA 1 transcript confers antitoxity which in any other case as in the formation of a helix instead of the stem loop fails to do. The result might be change in properties that make the RNA unsuitable for translation5.
On the other hand, intermolecular interactions, where a regulator RNA binds to a target RNA via complementary base pairing results in downstream regulatory consequences i.e the formation of the double helix and preventing the binding of protein to target or the formation of the helix itself facilitating binding of proteins like nucleases that in turn degrade the RNA and consequentially affect expression. Alternatively, what can be the case with regulation at the intermolecular level amongst RNA is that the duplex formation might be sequestering a region of the target that would have otherwise taken an alternative secondary structure required for its activity1. Topics in the article will discuss the various forms of RNA found to play key regulatory roles, many of them are involved in key intermolecular interactions that affect expression and hence find implication in human diseases.
MicroRNAs
MicroRNAs – short (22 bases) RNA molecules that play a key role in regulation at the translational level. A few are known to bind to promoter regions of genes and affect transcription. A total of about a 1000 genes in the human genome code
Finally it was found that a total of 62.1 % to about a 74.7% of the human genome was covered by either proceed or by the help of primary transcript.
Recent advantages in genome-wide analyses have revealed that roughly 90% of the human genome is transcribed, yet less than 3% of the genome consists of protein-coding genes (Wu et al., 2013). The remaining genes are transcribed as noncoding RNAs (ncRNAs), which resemble mRNA in length and splicing structures yet do not encode any proteins (Wu et al., 2013). It has been debated whether all of the ncRNA transcripts are functional due to their low expression levels and low evolutionary conservation. However, many functional ncRNA have
MicroRNAs (miRNA) are small noncoding RNA, usually 17-25 nucleotides long that are able to bind complementary sequences of target messenger RNA (mRNA) and to induce both their degradation and translational repression (Fortunato, et al 2014). They are one of the most significant classes of non-coding RNA molecules (eg. small interfering RNA (siRNA) and ribozymes) that act within the cell. MiRNAs are also evolutionary conserved in different species from plants to humans and are encoded by their respective genes (Bader, 2012).
Dr. Tina Henkin’s seminar “Flipping the switch: How cells use RNA to regulate genes expression”, was outlined by four general questions. The first question addressed in the seminar was “Why study Microbes?”. The next, “Why study bacterial gene regulation?”. The third question, “What are the basics of gene expression?”. Finally, “What’s special about riboswitches?”. Dr. Henkin addressed these questions throughout her seminar, which eventually led into to more specific questions of gene expression and predicted hypotheses of her model. However, to understand these more specific questions and predictions it is crucial to understand the first four questions outlined in the beginning of the seminar.
siRNA are a form of molecular RNA, they are formed from a long double stranded piece of RNA. The dsRNA is cleaved into siRNA segments by the endonuclease DICER, these segments range from 21-25 nucleotides in length. The siRNA becomes part of the RISC complex, one strand is removed, and the remaining strand binds to its exact compliment in the mRNA. At this point exonucleases will enter and degraded the cleaved mRNA.
In the second paper, “Novel RNA Modifications in the Nervous System: Form and Function,” Lee discusses the role of several novel RNA modification in the physiological setting of the nervous system. RNA editing plays a major role in many pathologies; for example, loss of normal function in an m6a demethylase, FTO, has been connected with cancer, ADHD, and Alzheimer’s. Other RNA modifications are necessary for proper development of the central nervous system. NSUN2 is an m5C RNA modification heavily implicated in embryogenesis, especially in the brain. Mutation of the NSUN2 gene is correlated with intellectual disability, developmental delay, and facial dysmorphism. The aforementioned A-to-I RNA edit is also enriched in the brain, and is necessary for the proper function of genes such as GluA2, which without modification leads to postnatal death. GluA2 is also implicated in glutamate reception by neurons, and consequently in the mechanisms of addiction. Furthermore, A-to-I RNA editing failure been linked with several chronic diseases, including
This study shows that 6% of the entire annotated non-coding and coding gene transcripts are overlapping with small RNAs. Highly specific subcellular positioning is found for both unannotated & annotated short RNA.
RNA interference takes advantage of an intermediate step between DNA and protein. DNA acts as a blueprint for the final protein by using messenger RNA (mRNA) . The mRNA is a messenger molecule between DNA and protein synthesis. There is a two steps process need to be completed in order to go from gene to protein. The first step in protein synthesis is transcription, it takes place in a cell’s nucleus, where the DNA template is used to make a single strand of mRNA. Then, the messenger RNA exits the nucleus and enters the cytoplasm. Now it serves as the template for making the protein. After that, with the help of several different molecules, a string of amino acids forms due to the order of the mRNA bases. This process is called translation
R5 spin labels were placed within a “kink-turn motif” site where the internal loop between nucleotides that are not base paired (Figure 2). This site was held constant throughout the study in both the 20-nucleotide RNA study and the 232-nucleotide mRNA study. Both the synthetic 20-nucleotide long mRNA and the R5 spin label precursor were purchased from lab companies; the mRNA was purchased from Dharmacon, and the R5 spin labels were purchased from Toronto Research Chemicals. The sequence of the mRNA had a phosphorothioate modification and was made specific to accompany a site that was open to binding with R5 spin labels.8 To ensure that the sample of mRNA has been effectively labeled, a high molar concentration ratio of spin label to
While humans are obviously different from many other mammals, such as dogs or mice, about 5% of the human genome consists of conserved sequences shared by all mammals. Interestingly, over two thirds of these sequences do not code for protein, but this does not necessarily mean that they are non-functional. One likely possibility is that these non-coding regions conserved throughout the mammalian genome function in genetic regulation. However, before determining the function of these regions within the genome, they must first be identified. After determining the conserved sequences, they can then be classified according to function. One particularly informative way to decipher the function of a non-coding DNA sequence is to determine
Transcription is a process in which information in a strand of DNA is copied to a new molecule of messenger RNA. DNA stores genetic material in the nuclei of cells. RNA is a copy of the original DNA material but is not used for long term storage and is free to exit the nucleus. Although it is not an exact copy of the DNA segment. Transcription is carried out by an enzyme called RNA polymerase and proteins called transcription factors. Newly formed mRNA copies of genes serve as blueprints for protein synthesis during translation.
RNA is very similar to DNA. It resembles a long chain with the links in the chain made up of individual nucleotides. The nucleotides in RNA also similar to DNA that made up of three components, which are a sugar, phosphate group, and a nitrogen base. The sugar in RNA is ribose instead of the more stable deoxyribose in DNA, which helps to make RNA more flexible and less durable. In RNA, the bases also come in four chemical forms, and the information in RNA is encoded in the sequence in which these bases are arrange. The nitrogen bases in RNA include Adenine (A), Cytosine (C), and Guanine (G), but RNA has Uracil (U) instead of Thymine (T) in DNA. Cells make RNA messages in a process similar to the replication of DNA. The DNA strands are pulled
One of the fundamental discoveries of the 20th century was that DNA was the genetic code’s physical structure (Watson & Crick, 1953) and, since then, many studies have disclosed the complicated pattern of regulation and expression of genes, which involve RNA synthesis and its subsequent translation into proteins.
Messenger RNA (mRNA) is extremely important in expression of protein-coding genes. mRNA molecules contain the genetic code for synthesis of particular polypeptides during translation. (Lewin’s Genes XI, 624) Messenger RNAs are unstable molecules due to the fact that cells have ribonucleases. These ribonucleases can specifically target mRNA molecules in the cytoplasm. There are two types of ribonucleases. Endoribonucleases cut the center of the RNAs, and exoribonuleases detach the ends of RNAs. (Lewin’s Genes XI, 625) The stability of mRNA is essential in controlling gene expression. Less stable RNAs are more likely to undergo changes in transcription rates, and the more stable RNAs are able to go through translation for longer periods of time. (Lewin’s Genes XI, 626)
There is said to be some 12,000 genes contained in eukaryotic cells, these cells need to be expressed in different forms. Gene expression can be a complex process that happens naturally throughout the body, to insure that everything functions perfectly, or to keep our bodies healthy. But what is gene expression? This is best described as genes in the body becoming active (also referred to as being turned on) and creating a product of some sort. The product that that was created during this time can be a protein, a molecule or an enzyme. In eukaryote cells this can be done in several different methods, one being alteration of the rate in with RNA transcripts are processed within the nucleus. It can also be done through altering the messenger RNA molecules, making them unstable so they degrade at different rates. The third way in which gene regulation is express in eukaryotic cells is by affecting the time it takes for ribosomes to translate mRNA into polypeptide. This is all