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The Evolution of Anticancer Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
It is also worth noting that the discrepancy between the originally estimated 100,000 or more functional genes in the human genome compared to the 30,000–40,000 identified through the HGP was originally ascribed to the presence of “junk” DNA in humans that serves no useful purpose. However, more recent studies have suggested that junk DNA may have a function in helping to re-locate critical genes in the genome during cell division. Regarding the identification of SNPs associated with diseases, these have been very useful as drug targets, particularly in the oncology area. This approach has led to some highly effective anticancer agents such as imatinib (GleevecTM) and crizotinib (AlkoriTM). Although many more anticancer agents are in development based on SNPs found in tumor cells, this approach is also producing results in other therapeutic areas such as asthma, Alzheimer’s disease, depression, and diabetes. Some examples of the genomic methodologies used in this new era of drug discovery are briefly described below.
Nucleic Acids
Published in Danilo D. Lasic, LIPOSOMES in GENE DELIVERY, 2019
The size of a genome can vary from small chromosomes of a virus containing around 5000 base pairs (bp), to around 4 million for Escherichia coli, while the 46 human chromosomes contain coding for almost 105 different proteins encoded in about 3 billion bp. It is estimated that approximately 10 trillion cells of the human body contain about 100,000 genes each. Differential transcription of genes during embriogenesis and between different cell types and organs is responsible for maintaining the specialization of the cell types. However, in humans around 97% of the DNA does not code for any proteins. It is likely that this DNA, which is often called junk DNA, is not (completely) wasteful and that it contains important information about temporal and structural events, such as regulation of gene expression. Some of it forms telomers which protect the ends of chromosomes and centromers which are attachment sites for spindles. Gene regulators turn on the right genes, at the right places, at the right times and allow, in addition, genes to be switched on and off by some environmental factors, such as concentration changes of some peptides, proteins, hormones, or simple molecules, like sugars. Some of the DNA stretches may act as membrane (nuclear matrix) attachment sites, while others may be important in DNA packaging. The length of the junk DNA varies from species to species. For instance, salamanders have 40 times longer DNA than humans while puffin fish have an eight-fold shorter genome than similar vertebrates (Holmes, 1995).
The mitotic phase of spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
The previous sections have revealed the importance of protein as intrinsic factors in regulating the mitotic phase of spermatogenesis. However, the involvement of genes/nucleic acid should not be overlooked. Mammalian genome analyses show that the protein-coding genes only contribute to 5%–10% of the genome. However, the remaining >90% of the genome are not junk DNA. Rather, these regions are actively transcribed into RNA, which is classified as noncoding RNA (ncRNA). Depending on the size/nucleotide (nt) length, ncRNA can be further divided into long (lncRNA; >200 nt) or short (<200 nt) ncRNA. Short ncRNA, such as PIWI-interacting RNA (piRNA), plays important roles in silencing retrotransposon and safeguarding the germline genome during meiotic progression.90 MicroRNA (miRNA) is another class of short ncRNA that is well reported to regulate gene expression posttranscriptionally by binding to the untranslated region of the mRNA. lncRNAs are expressed from a wide variety of genomic locations. They can be expressed from both autosomes and sex chromosomes in either sense or antisense direction. They can be either intergenic or in association with a gene at the promoter, exon, intron, or the untranslated region. Given their broad spectrum of expression, lncRNAs play versatile roles in a range of cellular processes. lncRNAs can act as baits to attract the binding of transcription factors and impair their interaction with DNA and hence their functions. lncRNAs can also act as decoys for RNA species. The binding of lncRNA to mRNA can regulate their degradation and nuclear export. The binding of lncRNA to miRNA can perturb their binding to bona fide mRNA targets and thus inhibit their activity. As well, the binding of lncRNA to genomic DNA has also been shown to recruit epigenetic modifiers that modulate epigenetic events such as methylation and histone modification. Finally, lncRNA acts as a precursor that after further processing by RNase will give rise to miRNA. This property provides a reservoir of miRNA without transcription.91 Intriguingly, emerging evidence has suggested that both the miRNA and lncRNA are involved in regulating the mitotic phase of spermatogenesis.
Developments in lncRNA drug discovery: where are we heading?
Published in Expert Opinion on Drug Discovery, 2018
Ilya Blokhin, Olga Khorkova, Jane Hsiao, Claes Wahlestedt
The central dogma of molecular biology, stating that the only role of the RNA transcripts is to convey information from gene to protein, was proposed by Crick [1] just a few years after he and Watson discovered the DNA structure. For a long time the only accepted types of RNA with no coding potential were ribosomal RNA (rRNA) and transport RNA (tRNA) that are components of translational machinery. Throughout this period, noncoding sequences that constitute more than 98% of the mammalian genome were considered nonfunctional ‘junk DNA’. It was therefore unexpected to discover that transcriptomes of most species encode multiple non-coding transcripts critical for fundamental cellular processes. Only a few scientists had an exceptional insight to predict that genome may encode multiple noncoding features with functions yet to be imagined [2,3]. In 1970s, small nuclear RNAs (snRNAs) were found to be indispensable for removal of introns from mRNA. snRNAs are abundant nonpolyadenylated transcripts, about 150 nucleotides in length, that build the core of major and minor spliceosomes. At approximately the same time, small nucleolar RNAs (snoRNAs), another class of noncoding RNAs, approximately 60–200 nucleotides in length, was discovered. snoRNAs include two families, C/D and H/ACA, that function in concert to posttranscriptionally edit (methylate, pseudouridylate, etc.) ribosomal RNA. In addition, snoRNAs can interact with and modify snRNAs [4], tRNAs [5], and protein-coding RNA [6].
Epigenetic regulatory modifications in genetic and sporadic frontotemporal dementia
Published in Expert Review of Neurotherapeutics, 2018
Chiara Fenoglio, Elio Scarpini, Daniela Galimberti
Previously, it was widely believed that most of the human genome did not have a coding potential and was thus referred as ‘non-functional’ DNA. It is now ascertained that most of this ‘junk’ DNA is instead functional and is transcribed in ncRNA, whose signaling and editing is able to play a crucial role in chromatin and nuclear structure. In particular, ncRNAs are involved in epigenetic regulation by recruiting chromatin-modifying complexes. ncRNAs operate through repressive control but have also the potential to act as gene activators [34]. The family comprises small RNAs (sRNAs) of less than 200 nucleotides and lncRNAs of more than 200 nucleotides. sRNA are further subdivided inmiRNAs, short interfering RNAs (siRNAs) and PIWI-associated RNAs (piRNAs), whereas lncRNAs are categorized according to their direction and position of their transcription in antisense (AS), intergenic, exonic, intronic, overlapping [35].
The discovery and development of RNA-based therapies for treatment of HIV-1 infection
Published in Expert Opinion on Drug Discovery, 2023
Michelle J Chen, Anne Gatignol, Robert J. Scarborough
The original function of RNA as a messenger between DNA and protein was elucidated in the mid-20th century [35]. It later became clear that these coding RNAs, or mRNAs, represent only a tiny percentage of the human DNA genome with the remainder initially being considered as ‘junk DNA’ [36]. By the beginning of the 21st century, it became clear that most ‘junk DNA’ is transcribed and in the past couple of decades the diverse and essential roles of non-coding RNAs in cell biology have begun to be uncovered [37]. The functional roles of non-coding RNAs have also been the inspiration for a number of RNA therapies. In this section, we summarize the development of non-coding RNAs as potential therapies for the treatment of HIV-1.