A GC box is also known as a GSG box.
A "GC box is a distinct pattern of nucleotides found in the promoter region of some eukaryotic genes upstream of the TATA box and approximately 110 bases upstream from the transcription initiation site. It has a consensus sequence GGGCGG which is position dependent and orientation independent. The GC elements are bound by transcription factors and have similar functions to enhancers."
A "repeating sequence of nucleotides that forms a transcription or a regulatory signal" is a box.
GC box theory
"GC-rich genomic sequences [include those] such as Alu repeats."
"An Alu element is a short stretch [2-8 nucleotides] of DNA originally characterized by the action of the Alu (Arthrobacter luteus) restriction endonuclease. Alu elements of different kinds occur in large numbers in primate genomes. In fact, Alu elements are the most abundant transposable elements in the human genome."
"The Alu family is a family of repetitive elements in the human genome. Modern Alu elements are about 300 base pairs long and are therefore classified as short interspersed elements (SINEs) among the class of repetitive DNA elements. The typical structure is 5'Part A- A5TACA6 -Part B - PolyA Tail - 3', where Part A and Part B are similar peptide sequences, but of opposite direction."
There are over one million Alu elements interspersed throughout the human genome, and it is estimated that about 10.7% of the human genome consists of Alu sequences. However less than 0.5% are polymorphic.
Alu elements are retrotransposons and look like DNA copies made from RNA polymerase III-encoded RNAs. Alu elements do not encode for protein products and depend on LINE retrotransposons for their replication.
"Alu elements in primates form a fossil record that is relatively easy to decipher because Alu elements insertion events have a characteristic signature that is both easy to read and faithfully recorded in the genome from generation to generation. The study of Alu elements thus reveals details of ancestry because individuals will only share a particular Alu element insertion if they have a common ancestor."
Most human Alu element insertions can be found in the corresponding positions in the genomes of other primates, but about 7,000 Alu insertions are unique to humans.
"Full-length Alu elements are ~300 bp long and are commonly found in introns, 3 untranslated regions of genes and intergenic genomic regions". Human subfamilies include Y, Yc1, Yc2, Ya5, Ya5a2, Yb8, and Yb9. A source of simple sequence repeats is an A-rich region "that contains the sequence A5TACA6".
"[T]here are ~24 CpG positions in a new Alu insertion ... the decay of methylated CpG dinucleotides into TpG dinucleotides would also tend to increase the pair-wise divergence between Alu repeats over time, thereby decreasing the recombination between elements."
"CpG sites or CG sites are regions of DNA where a cytosine nucleotide occurs next to a guanine nucleotide in the linear sequence of bases along its length. "CpG" is shorthand for "—C—phosphate—G—", that is, cytosine and guanine separated by only one phosphate; phosphate links any two nucleosides together in DNA. The "CpG" notation is used to distinguish this linear sequence from the CG base-pairing of cytosine and guanine. The CpG notation can also be interpreted as the cytosine being 5 prime to the guanine base." "The "p" in CpG refers to the phosphodiester bond between the cytosine and the guanine, which indicates that the C and the G are next to each other in sequence, regardless of being single- or double- stranded. In a CpG site, both C and G are found on the same strand of DNA or RNA and are connected by a phosphodiester bond. This is a covalent bond between atoms, stable and permanent as opposed to the three hydrogen bonds established after base-pairing of C and G in opposite strands of DNA."
There are regions of the genome that have a higher concentration of CpG sites, known as CpG islands. Many genes in mammalian genomes have CpG islands associated with the start of the gene (promoter regions). Because of this, the presence of a CpG island is used to help in the prediction and annotation of genes.
"The usual formal definition of a CpG island is a region with at least 200 [base pair] bp, and a GC percentage that is greater than 50%, and with an observed-to-expected CpG ratio that is greater than 60%. The "observed-to-expected CpG ratio" is calculated by formula ((Num of CpG/(Num of C × Num of G)) × Total number of nucleotides in the sequence).
In mammalian genomes, CpG islands are typically 300-3,000 base pairs in length, and have been found in or near approximately 40% of promoters of mammalian genes. About 70% of human promoters have a high CpG content. Given the frequency of GC two-nucleotide sequences, the number of CpG dinucleotides is much lower than would be expected.
"CpG islands are characterized by CpG dinucleotide content of at least 60% of that which would be statistically expected (~4–6%), whereas the rest of the genome has much lower CpG frequency (~1%), a phenomenon called CG suppression. Unlike CpG sites in the coding region of a gene, in most instances the CpG sites in the CpG islands of promoters are unmethylated if the genes are expressed."
"Cytosines in CpG dinucleotides can be methylated to form 5-methylcytosine. In mammals, methylating the cytosine within a gene can turn the gene off, a mechanism that is part of a larger field of science studying gene regulation that is called epigenetics. Enzymes that add a methyl group are called DNA methyltransferases."
In mammals, 70% to 80% of CpG cytosines are methylated.
"CpG dinucleotides have long been observed to occur with a much lower frequency in the sequence of vertebrate genomes than would be expected due to random chance. For example, in the human genome, which has a 42% GC content, a pair of nucleotides consisting of cytosine followed by guanine would be expected to occur 0.21 * 0.21 = 4.41% of the time. The frequency of CpG dinucleotides in human genomes is 1% — less than one-quarter of the expected frequency."
Unmethylated CpG sites can be detected by Toll-Like Receptor 9 "(TLR 9) on plasmacytoid dendritic cells and B cells in humans. This is used to detect intracellular viral, fungal, and bacterial pathogen DNA."
Methylation is central to imprinting, along with histone modifications. Most of the methylation occurs a short distance from the CpG islands (at "CpG island shores") rather than in the islands themselves.
Methylation of CpG sites within the promoters of genes can lead to their silencing, a feature found in a number of human cancers (for example the silencing of tumor suppressor genes). In contrast, the hypomethylation of CpG sites has been associated with the over-expression of oncogenes within cancer cells.
The CpG deficiency is due to an increased vulnerability of methylcytosines to spontaneously deaminate to thymine in genomes with CpG cytosine methylation.
Alu elements are a common source of mutation in humans, but such mutations are often confined to non-coding regions where they have little discernible impact on the bearer.
The first report of Alu-mediated recombination causing a prevalent inherited predisposition to cancer was a 1995 report about hereditary nonpolyposis colorectal cancer.
"The human diseases caused by Alu insertions include":
- Breast cancer
- Ewing's sarcoma
- Familial hypercholesterolemia
- Diabetes mellitus type II.
The following diseases have been associated with single-nucleotide DNA variations in Alu elements impacting transcription levels:
The ACE gene, encoding angiotensin-converting enzyme, has 2 common variants, one with an Alu insertion (ACE-I) and one with the Alu deleted (ACE-D). This variation has been linked to changes in sporting ability: the presence of the Alu element is associated with better performance in endurance-oriented events (e.g. triathlons), whereas its absence is associated with strength- and power-oriented performance
The opsin gene duplication which resulted in the re-gaining of trichromacy in Old World primates (including humans) is flanked by an Alu element, "implicating the role of Alu in the evolution of three colour vision."
"A GC box sequence, one of the most common regulatory DNA elements of eukaryotic genes, is recognized by the Spl transcription factor; its consensus sequence is represented as 5'-G/T G/A GGCG G/T G/A G/A C/T-3' [or 5′-KRGGCGKRRY-3′] (Briggs et al., 1986)."
Transcription start sites
"In promoters containing multiple GC boxes but lacking the TATAA box, transcription start sites may be single and specific, as observed in the nerve growth factor receptor gene (42) and the cellular retinol-binding protein gene (37), or there may be multiple heterogeneous start sites, such as those found in the c-myb (4), insulin receptor (45), and Ha-ras (21) genes. ... GC boxes are responsible for directing transcription from the major and the minor start sites. ... All TATAA-less promoters have at least two GC boxes".
"CpG islands typically occur at or near the transcription start site of genes, particularly housekeeping genes, in vertebrates. Normally a C (cytosine) base followed immediately by a G (guanine) base (a CpG) is rare in vertebrate DNA because the cytosines in such an arrangement tend to be methylated. This methylation helps distinguish the newly synthesized DNA strand from the parent strand, which aids in the final stages of DNA proofreading after duplication. However, over evolutionary time methylated cytosines tend to turn into thymines because of spontaneous deamination. While there is a special enzyme in human (Thymine-DNA glycosylase, or TDG) that specifically replaces T's from T/G mismatches, it is not sufficiently effective to prevent the relatively rapid mutation of the dinucleotides. The result is that CpGs are relatively rare. The existence of CpG islands is usually explained by the existence of selective forces for relatively high CpG content, or low levels of methylation in that genomic area, perhaps having to do with the regulation of gene expression. Recently a study showed that most CpG islands are a result of non-selective forces. "
"[A] GC box-binding factor is required for transcription and ... a truncated promoter containing one GC box is transcriptionally inactive (44). ... the DNA-protein interactions occurring at the GC boxes in the DHFR promoter are functionally distinct and that factors binding to the GC boxes must interact in a position-dependent manner."
"A large subclass of polymerase II promoters lacks both TATAA and CCAAT sequence motifs but contains multiple GC boxes. This promoter class includes several housekeeping genes (e.g., the genes encoding dihydrofolate reductase [DHFR] ..., hydroxymethylglutaryl coenzyme A reductase , hypoxanthine guanine phosphoribosyltransferase , and adenosine deaminase ) [and] nonhousekeeping genes (e.g., the transforming growth factor alpha [9, 23], rat malic enzyme , human c-Ha-ras , epidermal growth factor receptor , and nerve growth factor receptor  genes)."
- The GC box does not indicate the TSS for A1BG.
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