Mutations - DNA Repair and Mutagenesis - Essay Example

MIs culminate in the creation of loops possessing extra-helical bases that can produce frame-shift mutations unless they are reversed by mismatch repair (Errol et al 54). In HNPCC, also known as Lynch syndrome, an inherited mutation located in the mismatch repair gene leads to MI replication errors going unfixed. In most cases, this results in length changes for di-nucleotide repeats for the nucleo-bases adenine and cytosine. Changes in the nucleotide repeats indicate a DNA repair system in fault that can lead, to the growth of colon cancer cells. MI insertions and deletions cause inappropriate DNA repair, which leads to uncontrolled division of cells and the growth of tumors. This paper provides examples of human diseases that result from mutations and the way these mutations give rise to the diseases.

            Mutations affecting transition in CpG islands are a common cause of colorectal cancer. O6-methyl-guanine DNA methyl-transferase, or MGMT, is a vital enzyme during the repair of DNA. The enzyme removes all cytotoxic and mutagenic adducts from O6-guanine found in DNA. This site is the most preferred attack point for numerous alkylating chemotherapeutic agents and carcinogens. The loss of MGMT activity can be triggered by hyper-methylating the CpG Island that is located in MGMT’s promoter region and is culpable in most cases of colorectal cancer (Errol et al 71). Silencing of MGMT via methylation portends two consequences for colorectal cancer. Tumors, which have methylated MGMT possess a new mutator phenotype that is characterized by transition point mutation generation in genes concerned related to cancer etiology. Examples of these genes are oncogene K-ras and tumor suppressor p53. In addition, hyper-methylation of MGMT can be used in pharmaco-epigenomics with methylated tumors showing more sensitivity to alkylating drugs utilized in chemotherapy (Errol et al 71).

            Another form of mutation can occur during alternative splicing, which causes Oculopharyngeal muscular dystrophy, or OPMD. This disease is an autosomal dominant disease of the muscles, which occurs worldwide. Recent research has found that the disease’s genetic basis is in mutations to the poly-A binding protein gene, which involves short GCQ tri-nucleotide repeat expansions that encode the poly-alanine tract (Schwarz 76). The underlying mechanism, which causes triplet expansion of mutation of the gene, is yet to be elucidated, but the model of DNA slippage is thought to be a plausible explanation. Mutated alleles found in patients suffering from OPMD are most likely caused by (GCG)(2)(GCA)(3) and (GCG)(3)GCA and not because of GCG repeat expansions (Schwarz 78). Unequal crossing-over of the two PABP2 alleles, therefore, rather than slippage of DNA, is the best explanation for mutations that lead to OPMD. Practically, all mutations that patients with OPMD report are explained by unequal crossover.

            Mutations occurring during alternative splicing can cause breast cancer. Breast cancer cells, as do most other cancer cells, adapt to their environment via the generation of new genetic products by alternative splicing (Jeanteur 80). Analysis of transcriptome has shown that over fifty percent of the human genome encodes protein isoforms by alternative splicing of pre- mRNA. Therefore, alternative splicing is utilized as a vital mechanism for the generation of human proteome diversity. Additionally, the isoform-selective expression of genes is important in cellular phenotype since splice isoforms have opposite or distinct functions. In breast cancer cells, there are numerous instances of variant deregulation and the cells express aberrant products from alternative splicing mutations that are uncommon in normal cells (Jeanteur 80). Mutations in alternative splicing; therefore, are used, by cells, to improve their protein repertoire, which enables them to grow into breast cancer cells.

            Over one hundred and eighty mutations have been identified in the GALT gene, in people with classic galactosemia. The majority of the mutations have effects in that they eliminate or severely reduce the activity of the enzyme galactose-1-phosphate uridyl-transferase (Rosenberg 122). Shortages in these enzymes stop cells from processing the sugar galactose that they get from the diet. Consequently, galactose-1phosphate and other related compounds are allowed to reach toxic levels in the blood. With the accumulation of these related substances, tissue and organ damage results lead to serious medical conditions that are related to classic galactosemia.

            Most mutations to the GALT gene change a single amino acid that is used in building the enzyme. The most common form of GALT mutation in white North Americans and Europeans replaces glutamine with arginine at position 188 of the enzyme (Rosenberg 122). Another GALT mutation occurs almost entirely among the African populace. In this mutation, leucine is substituted for serine at position 135. Another GALT mutation does exist, the Duarte variant leads to a form of galactosemia that has fewer complications. The mutation leads to the replacement of asparagine with aspartic acid at position 314 (Rosenberg 123). This variant reduces, without eliminating, the activity of the enzyme. Its signs and symptoms tend to be a little pronounced since the enzyme retains five to twenty percent of normal activity.