dna repair mutagenesis and other responses to dna damage pdf

Dna Repair Mutagenesis And Other Responses To Dna Damage Pdf

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Nataliya V.

DNA Damage and Repair

The integrity of the genome is essential to the health of the individual and to the reproductive success of a species. Transmission of genetic information is in a selective balance between two opposing forces, the maintenance of genetic stability versus elimination of mutational change and loss of evolutionary potential. Caenorhabditis elegans provides many advantages for the study of DNA surveillance and repair in a multicellular organism.

Several genes have been identified by mutagenesis and RNA interference that affect DNA damage checkpoint and repair functions.

Many of these DNA damage response genes also play essential roles in DNA replication, cell cycle control, development, meiosis and mitosis. To date, no obvious DNA damage-induced checkpoint has been described in C. In contrast, the DNA damage response in the germ line is characterized by two spatially separate checkpoints; mitotic germ nuclei proliferation arrest and apoptosis of damaged meiotic nuclei.

Both of these responses are regulated by checkpoint genes including mrt-2 , hus-1 , rad-5 and cep-1 , the C. The germ line DNA damage checkpoints in C. In addition to single gene studies, integration of data from high-throughput screens has identified genes not previous implicated in the DNA damage response and elucidated novel connections between the different repair pathways. Most of the genes involved are conserved between worms and humans, and in humans, are associated with either oncogenesis or tumor-suppression.

Thus, studies of the physical and functional interactions of the components of the repair pathways in C. Faithful transmission of genetic information is in a selective balance between genetic stability and mutational change as a resource for evolutionary potential. In order to maintain genome fidelity the coordinated action of surveillance and repair pathways is required. Much of our knowledge about repair has come from studies in bacteria, yeast and mammals, including human cell lines reviewed in Sancar et al.

Caenorhabditis elegans provides an experimental model in which the repair processes required for both genomic stability and mutational change can be studied. In this Chapter, we present an overview of DNA damage response research using Caenorhabditis elegans. Table 1 is a summary of some DNA damage response genes identified in the C. Included in the Table are components of the pathways for nucleotide excision repair, mismatch repair, DNA damage checkpoint, non-homologous end joining, homologous recombination repair, and chromosomal structure surveillance.

In addition to those listed in Table 1 are those genes involved in base excision repair, DNA glycosylation, the rad-6 pathway, trans-lesion bypass, and those encoding editing and processing nucleases. UV irradiation of the Rad mutants results in a decrease in viability. Many of these Rad mutants exhibit phenotypes in addition to their UV sensitivity suggesting that the Rad genes are involved in other biological processes in addition to their roles in the UV-induced DNA damage response Table 1.

More recently, researchers have used reverse genetic techniques such as RNA interference and PCR-mediated gene knockouts to investigate genes involved in different DNA damage response pathways such as nucleotide excision repair Park et al.

The UV sensitivity of C. The UV hypersensitivity of the early stage embryo might be due in part to the rapid cell proliferation and the lack of obvious DNA damage-induced checkpoints; DNA replication progresses even after exposure to large fluences of UV radiation Jones and Hartman, In contrast to the developing embryo, activation of the checkpoint in the germ line results in obvious morphological changes that can be monitored by microscopy of live animals.

Gartner et al. In the meiotic region of the germ line, cells with DNA damage are removed by apoptosis before oogenesis. DNA damage-induced apoptosis occurs in addition to physiological programmed germ cell death, which is hypothesized to maintain germline homeostasis. DNA damage-induced germ cell death requires the conserved apoptotic machinery Gartner et al.

However, the proapoptotic gene egl-1 , which is required for somatic programmed cell death but not physiological germ cell death, is not absolutely required for DNA damage-induced germ cell apoptosis Gartner et al. The specific genes involved in the germline DNA damage-induced checkpoints are shown in Figure 1 and are discussed below. Figure 1. Diagram of the germline DNA damage-induced checkpoints.

An exciting finding was the identification of mrt-2 , a gene responsible for germline immortality Ahmed and Hodgkin, In addition, mrt-2 mutants are defective in DNA damage-induced mitotic arrest and apoptosis in the germline Gartner et al. In addition to mrt-2 , function of the DNA damage checkpoint involves the gene hus-1 , which when mutated results in a phenotype similar to mrt-2 Hofmann et al.

Another checkpoint gene is rad-5 Gartner et al. Cloning of the rad-5 gene Ahmed et al. Overexpression of human CLK2 in C. Ahmed and coworkers suggest that the differences observed in the three studies could be explained by the fact that telomere length varies considerably between C. Cheung et al. Furthermore, CEP-1 can induce apoptosis in mammalian cells and this induction can be inhibited by iASPP, an evolutionarily conserved inhibitor of p53 Bergamaschi et al.

Several genes have been identified that either regulate cep-1 activity or are regulated by cep The C. Lettre et al. Many of the genes identified in this screen required cep-1 activity for the increase in germ cell death. Deng et al. Deletion of abl-1 results in increased radiation-induced apoptosis, but not ethylnitrosourea-induced apoptosis.

In addition, treatment of C. In contrast to the Drosophila p53 ortholog, cep-1 has also been shown to regulate DNA damage-induced mitotic germ cell arrest B. Derry, personal communication. Furthermore, cep-1 -mediated germline mitotic arrest is dependent on phg-1 , a C.

Components of the mismatch repair pathway were originally identified in bacteria as mutation-prone strains. Utilizing a system to screen for repeat sensitivity, Tijsterman et al. In this screening system, a DNA repeat puts a heat-shock promoter-driven lacZ transgene reporter gene out of frame. Mutations that result in a frameshift would result in lacZ expression. Degtyareva et al. In this study, the phenotype of msh-2 mutants was similar to wild-type worms with regard to lifespan and meiotic chromosome segregation, but msh-2 animals had somewhat reduced fertility.

In addition, the mutant worms had reduced DNA damage-induced germ-line apoptosis after genotoxic stress, linking a functional component of the mismatch repair pathway to the DNA damage checkpoint in C. This result is similar to that observed in mammalian mismatch repair mutants reviewed in Buermeyer et al. Not all mismatch repair homologs have a role in DNA repair.

Similar to the situation in budding yeast, the C. Double-strand breaks DSBs occur in response to environmental insult, such as ionizing radiation or genotoxic chemicals, or cellular sources such as oxidative damage or replication blocks in the DNA.

In addition to their unwanted creation by DNA damaging events or substances, DSBs are created biologically by SPO as the highly regulated initiation of meiotic recombination. The processing of both categories of DSBs utilizes many of the same proteins and mechanisms. It is unclear whether the checkpoint kinase, chk-2 functions during DNA repair as well as during meiosis because of the severe meiotic phenotype of chk-2 loss of function mutants MacQueen and Villeneuve, RNAi depleted brc-1 and brd-1 worms had a high incidence of X-chromosome nondisjunction Him phenotype and increased germ cell death apoptotic phenotype.

In addition, radiation treatment resulted in increased apoptotic cell death, chromosome fragmentation, and radiation hyper-sensitivity, strongly implicating brc-1 in DNA damage response. Recently, a BRCA2-related gene has been identified and shown to be involved in double-strand break repair by homologous recombination like its mammalian counterpart. Martin et al. Whereas in mouse, loss of function of a related gene, Rtel regulator of telomere length showed telomere loss and displayed many chromosome breaks and fusions Ding et al.

In humans, Bloom's syndrome is an autosomal-recessive human disorder caused by mutations in the BLM RecQ helicase and is associated with loss of genomic integrity and an increased incidence of cancer. A third helicase, the C.

Lee et al. Irrespective of gamma-irradiation, pre-meiotic germ cells had an abnormal checkpoint response to DNA replication blockage. The authors point out that the wrn-1 RNAi phenotypes are similar to those of Werner syndrome; for example, premature aging and reduced body size, suggesting that C.

A broad perspective on genes involved in DNA repair has been gained using high throughput, genome-wide analysis of RNAi phenotypes in C. As part of a large scale analysis of protein-protein interactions, known proteins implicated in replication, nucleotide excision repair, mismatch repair, base excision repair, non-homologous end joining, homologous recombination and checkpoint pathways were used in yeast 2-hybrid experiments to identify physical interactors in the predicted proteome Boulton et al.

Results from this study illustrate how sensors, transducers and mediators are shared when generating different responses like chromatin remodeling, altered gene expression and DNA replication Figure 2. In a striking way, data from C. Figure 2. Yeast 2-hybrid data from Li et al. Data has been visualized by Maja Tarailo from the University of British Columbia, using Osprey , a software platform for visualizing complex interaction networks. Colours denote Gene Ontology GO terms.

Genes have been identified by mutagenesis and RNAi that affect DNA damage checkpoint and repair functions resulting in hypersensitivity to radiation. To date no obvious DNA damage-induced checkpoint has been described in the soma. In contrast, the DNA damage response in the germ line is characterized by two spatially separate checkpoint responses; mitotic germ nuclei proliferation arrest and cep-1 -mediated apoptosis of damaged meiotic nuclei. In addition to single gene studies, integration of data from high-throughput screens has identified genes not previously implicated in the DNA damage response and elucidated novel connections between the different repair pathways.

Ahmed, S. MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. Nature , — Abstract Article. Aoki, H. Alpi, A. Genetic and cytological characterization of the recombination protein RAD in Caenorhabditis elegans. Chromosoma , 6— Benard, C. Development , —

Historical Perspective on the DNA Damage Response

Martin L. Smith, Young R. The regulation of DNA excision repair pathways by p53 and its downstream genes is an emerging body of literature, largely distinct and separable from the more-studied cell cycle arrest and apoptosis responses regulated by p Regulation of nucleotide excision repair of UV-damage by p53 and its downstream genes Gadd45 and p48XPE has been well-documented, but much remains to be done in elucidating mechanisms. Moreover, p53 also participates in base excision repair of hydrogen peroxide-induced damage, still at an early stage of investigation. In human cancers carrying inactivating mutations in p53, especially those wherein p53 mutation occurs early, accelerated mutagenesis by exogenous and endogenous DNA damage is predicted. At the same time, the excision repair pathways could provide a useful target for DNA-damaging chemotherapeutics against pdefective cancers, having decreased ability to repair chemotherapeutic damage.


View Table of Contents for DNA Repair and Mutagenesis PDF · Request permissions. CHAPTER 1. no. Introduction: Biological Responses to DNA Damage (Pages: ) · Summary Managing DNA Strand Breaks in Eukaryotic Cells: Nonhomologous End Joining and Other Pathways (Pages: ).


Mechanisms of DNA damage, repair and mutagenesis

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Damage to cellular DNA is involved in mutagenesis and the development of cancer. The DNA in a human cell undergoes several thousand to a million damaging events per day, generated by both external exogenous and internal metabolic endogenous processes. Changes to the cellular genome can generate errors in the transcription of DNA and ensuing translation into proteins necessary for signaling and cellular function.

The genomic integrity of every organism is constantly challenged by endogenous and exogenous DNA-damaging factors. Mutagenic agents cause reduced stability of plant genome and have a deleterious effect on development, and in the case of crop species lead to yield reduction. It is crucial for all organisms, including plants, to develop efficient mechanisms for maintenance of the genome integrity. DNA repair processes have been characterized in bacterial, fungal, and mammalian model systems. The description of these processes in plants, in contrast, was initiated relatively recently and has been focused largely on the model plant Arabidopsis thaliana.

DNA Repair Mechanisms and Their Biological Implications in Mammalian Cells

DNA damage and repair

The integrity of the genome is essential to the health of the individual and to the reproductive success of a species. Transmission of genetic information is in a selective balance between two opposing forces, the maintenance of genetic stability versus elimination of mutational change and loss of evolutionary potential. Caenorhabditis elegans provides many advantages for the study of DNA surveillance and repair in a multicellular organism. Several genes have been identified by mutagenesis and RNA interference that affect DNA damage checkpoint and repair functions. Many of these DNA damage response genes also play essential roles in DNA replication, cell cycle control, development, meiosis and mitosis. To date, no obvious DNA damage-induced checkpoint has been described in C.

Cellular DNA damage is implicated in the aetiology and progression of many different types of human disorders and diseases. Much of the current research in the DNA damage field is devoted towards understanding the mechanisms and biological implications of DNA lesions that turn into genetic mutations; mutations which ultimately lead to the development of cancer. The levels of DNA damage in cancer cells and in other diseased cells are elevated in comparison to the lesion levels found in normal cells.

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response to DNA damage, is activated to get rid of cells. with extensive genome Exogenous DNA damage, on the other hand, occurs when.


DNA damage (naturally occurring)

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages interstrand crosslinks or ICLs. The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:.

Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states. However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important. Preserving genomic sequence information in living organisms is important for the perpetuation of life.

DNA Damage and Repair
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