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Protecting cellular DNA from mutations

Protecting cellular DNA from mutations

About this article. Chromosomal landscape of UV damage formation and repair Proteting single-nucleotide resolution. Schuster-Bockler, B. Moores Cancer Center, UC San Diego, La Jolla, CA,USA. Douki, T. Specifically, substitutions were 1.

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How mutations, or variations, can lead to genetic conditions

Protecting cellular DNA from mutations -

For example, by examining the number of individuals in a given population who were diagnosed with neurofibromatosis NF1, a disease caused by a spontaneous—or noninherited—dominant mutation , scientists determined that the spontaneous mutation rate of the gene responsible for this disease averaged 1 x 10 -4 mutations per gamete Crowe et al.

Other researchers have found that the mutation rates of other genes , like that for Huntington's disease, are significantly lower than the rate for NF1. The fact that investigators have reported different mutation rates for different genes suggests that certain loci are more prone to damage or error than others.

Defects in DNA repair underlie a number of human genetic diseases that affect a wide variety of body systems but share a constellation of common traits, most notably a predisposition to cancer Table 2. These disorders include ataxia-telangiectasia AT , a degenerative motor condition caused by failure to repair oxidative damage in the cerebellum, and xeroderma pigmentosum XP , a condition characterized by sensitivity to sunlight and linked to a defect in an important ultraviolet UV damage repair pathway.

In addition, a number of genes that have been implicated in cancer, such as the RAD group, have also been determined to encode proteins critical for DNA damage repair. UV radiation causes two classes of DNA lesions: cyclobutane pyrimidine dimers CPDs, Figure 1 and photoproducts PPs, Figure 2.

Both of these lesions distort DNA's structure, introducing bends or kinks and thereby impeding transcription and replication.

Relatively flexible areas of the DNA double helix are most susceptible to damage. In fact, one "hot spot" for UV-induced damage is found within a commonly mutated oncogene , the p53 gene.

CPDs and PPs are both repaired through a process known as nucleotide excision repair NER. In eukaryotes, this complex process relies on the products of approximately 30 genes.

Defects in some of these genes have been shown to cause the human disease XP, as well as other conditions that share a risk of skin cancer that is elevated about a thousandfold over normal. More specifically, eukaryotic NER is carried out by at least 18 protein complexes via four discrete steps Figure 3 : detection of damage; excision of the section of DNA that includes and surrounds the error; filling in of the resulting gap by DNA polymerase; and sealing of the nick between the newly synthesized and older DNA Figure 4.

In bacteria which are prokaryotes , however, the process of NER is completed by only three proteins, named UvrA, UvrB, and UvrC. Bacteria and several other organisms also possess another mechanism to repair UV damage called photoreactivation. This method is often referred to as "light repair," because it is dependent on the presence of light energy.

In comparison, NER and most other repair mechanisms are frequently referred to as "dark repair," as they do not require light as an energy source. During photoreactivation, an enzyme called photolyase binds pyrimidine dimer lesions; in addition, a second molecule known as chromophore converts light energy into the chemical energy required to directly revert the affected area of DNA to its undamaged form.

Photolyases are found in numerous organisms, including fungi, plants, invertebrates such as fruit flies, and vertebrates including frogs.

Figure 4 NER and photoreactivation are not the only methods of DNA repair. For instance, base excision repair BER is the predominant mechanism that handles the spontaneous DNA damage caused by free radicals and other reactive species generated by metabolism.

Bases can become oxidized, alkylated, or hydrolyzed through interactions with these agents. For example, methyl CH 3 chemical groups are frequently added to guanine to form 7-methylguanine; alternatively, purine groups may be lost. All such changes result in abnormal bases that must be removed and replaced.

Thus, enzymes known as DNA glycosylases remove damaged bases by literally cutting them out of the DNA strand through cleavage of the covalent bonds between the bases and the sugar-phosphate backbone.

The resulting gap is then filled by a specialized repair polymerase and sealed by ligase. Many such enzymes are found in cells, and each is specific to certain types of base alterations. Yet another form of DNA damage is double-strand breaks, which are caused by ionizing radiation, including gamma rays and X-rays.

These breaks are highly deleterious. In addition to interfering with transcription or replication, they can lead to chromosomal rearrangements , in which pieces of one chromosome become attached to another chromosome.

Genes are disrupted in this process, leading to hybrid proteins or inappropriate activation of genes. A number of cancers are associated with such rearrangements. Double-strand breaks are repaired through one of two mechanisms: nonhomologous end joining NHEJ or homologous recombination repair HRR.

In NHEJ, an enzyme called DNA ligase IV uses overhanging pieces of DNA adjacent to the break to join and fill in the ends. Additional errors can be introduced during this process, which is the case if a cell has not completely replicated its DNA in preparation for division. In contrast, during HRR, the homologous chromosome itself is used as a template for repair.

Mutations in an organism's DNA are a part of life. Our genetic code is exposed to a variety of insults that threaten its integrity. But, a rigorous system of checks and balances is in place through the DNA repair machinery. The errors that slip through the cracks may sometimes be associated with disease, but they are also a source of variation that is acted upon by longer-term processes, such as evolution and natural selection.

Branze, D. Regulation of DNA repair throughout the cell cycle. Nature Reviews Molecular Cell Biology 9 , — doi pdf link to article. Crowe, F. A Clinical, Pathological, and Genetic Study of Multiple Neurofibromatosis Springfield, Illinois, Charles C. Thomas, Lodish, H. Molecular Biology of the Cell , 5th ed.

New York, Freeman, Sinha, R. UV-induced DNA damage and repair: A review. Photochemical and Photobiological Sciences 1 , — Genetically Modified Organisms GMOs : Transgenic Crops and Recombinant DNA Technology. Recombinant DNA Technology and Transgenic Animals. Restriction Enzymes.

The Biotechnology Revolution: PCR and the Use of Reverse Transcriptase to Clone Expressed Genes. DNA Replication and Causes of Mutation. Genetic Mutation. Major Molecular Events of DNA Replication. Semi-Conservative DNA Replication: Meselson and Stahl. Barbara McClintock and the Discovery of Jumping Genes Transposons.

Functions and Utility of Alu Jumping Genes. Transposons, or Jumping Genes: Not Junk DNA? Transposons: The Jumping Genes. DNA Transcription. RNA Transcription by RNA Polymerase: Prokaryotes vs Eukaryotes. Translation: DNA to mRNA to Protein. What is a Gene? Colinearity and Transcription Units.

Discovery of DNA as the Hereditary Material using Streptococcus pneumoniae. Discovery of DNA Structure and Function: Watson and Crick. Isolating Hereditary Material: Frederick Griffith, Oswald Avery, Alfred Hershey, and Martha Chase.

Copy Number Variation. Copy Number Variation and Genetic Disease. Copy Number Variation and Human Disease. DNA Deletion and Duplication and the Associated Genetic Disorders. The cycle goes on to produce cancer. Just think of it as releasing the brakes in a speeding car. Another type of gene that is often mutated to promote cancer is an oncogene.

Oncogenes have the potential to cause cancer, but only when they get mutated. Once mutated, oncogenes they promote or allow uncontrolled cell growth, which leads to cancer. Sites Duke Express is powered by WordPress. Read the Sites Duke Express policies and FAQs , or request help.

Mission to Mars Encounter with Radiation. Home About Resources Downloads. Search Search. Cells Protect Themselves from Damage to Their DNA The cell has many mechanisms to ensure that each DNA molecule replicates to form an identical copy. Figure 9. The figure above is an illus-tration of the human chromosomes, indicating the chromo-somal location 17 of the p53 gene that encodes the p53 protein.

Ultraviolet Protecting cellular DNA from mutations cellulat causes various types of DNA damage, which Insulin pump comparison to specific cellullar and the emergence csllular skin cancer Metabolism-boosting lifestyle humans, often decades after initial exposure. Anti-cancer inspiration UV wavelengths cause the Protectinf of prominent UV-induced Muations lesions. Most of these lesions are Protectkng by the nucleotide nutations repair pathway, which is defective in rare genetic skin disorders referred to as xeroderma pigmentosum. A major role in inducing sunlight-dependent skin cancer mutations is assigned to the cyclobutane pyrimidine dimers CPDs. In this review, we discuss the mechanisms of UV damage induction, the genomic distribution of this damage, relevant DNA repair mechanisms, the proposed mechanisms of how UV-induced CPDs bring about DNA replication-dependent mutagenicity in mammalian cells, and the strong signature of UV damage and mutagenesis found in skin cancer genomes. Ultraviolet light is a type of electromagnetic radiation invisible to the human eye. Protecting cellular DNA from mutations This page has been archived and is no longer updated. Protectihg addition to genetic insults caused by the environment, the very process fom DNA replication Protectlng cell Food miles reduction is Digestion support products to error. The rate mutatios which DNA polymerase Protecting cellular DNA from mutations incorrect nucleotides during DNA replication is a major factor in determining the spontaneous mutation rate in an organism. While a " proofreading " enzyme normally recognizes and corrects many of these errors, some mutations survive this process. Estimates of the frequency at which human DNA undergoes lasting, uncorrected errors range from 1 x 10 -4 to 1 x 10 -6 mutations per gamete for a given gene. A rate of 1 x 10 -6 means that a scientist would expect to find one mutation at a specific locus per one million gametes. Mutation rates in other organisms are often much lower Table 1.

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