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The New Phytologist Dec 2005As obligate phototrophs, plants harness energy from sunlight to split water, producing oxygen and reducing power. This lifestyle exposes plants to particularly high... (Review)
Review
As obligate phototrophs, plants harness energy from sunlight to split water, producing oxygen and reducing power. This lifestyle exposes plants to particularly high levels of genotoxic stress that threatens genomic integrity, leading to mutation, developmental arrest and cell death. Plants, which with algae are the only photosynthetic eukaryotes, have evolved very effective pathways for DNA damage signalling and repair, and this review summarises our current understanding of these processes in the responses of plants to genotoxic stress. We also identify how the use of new and emerging technologies can complement established physiological and ecological studies to progress the application of this knowledge in biotechnology.
Topics: Base Pair Mismatch; DNA Damage; DNA Repair; Genome, Plant; Photosynthesis; Plants; Recombination, Genetic; Ultraviolet Rays
PubMed: 16313635
DOI: 10.1111/j.1469-8137.2005.01548.x -
Clinical Cancer Research : An Official... Aug 2009Epigenetic silencing of essential components of DNA repair pathways is a common event in many tumor types, and comprise O6-methylguanine-DNA methyltransferase (MGMT),... (Review)
Review
Epigenetic silencing of essential components of DNA repair pathways is a common event in many tumor types, and comprise O6-methylguanine-DNA methyltransferase (MGMT), human mut L homolog 1 (hMLH1), Werner syndrome gene (WRN), breast cancer susceptibility gene 1 (BRCA1), and genes of the Fanconi anemia pathway. Most interestingly, some of these alterations become the Achilles heel of the affected tumors upon treatment with certain classes of anticancer agents. That is, patients whose tumors carry such defects can be stratified for respective therapy rendering some classic DNA damaging agents, such as alkylators or DNA crosslinking agents, into "targeted therapies." Here we review some of the affected repair pathways that, when inactivated, sensitize the tumors to specific drugs and are thus exploitable for individualized therapy.
Topics: Antineoplastic Agents; DNA Repair; Drug Delivery Systems; Epigenesis, Genetic; Humans; Models, Biological; Neoplasms; Signal Transduction
PubMed: 19671858
DOI: 10.1158/1078-0432.CCR-08-1169 -
Nature Reviews. Molecular Cell Biology Jul 2010Post-translational modification by ubiquitin is best known for its role in targeting its substrates for regulated degradation. However, non-proteolytic functions of the... (Review)
Review
Post-translational modification by ubiquitin is best known for its role in targeting its substrates for regulated degradation. However, non-proteolytic functions of the ubiquitin system, often involving either monoubiquitylation or polyubiquitylation through Lys63-linked chains, have emerged in various cell signalling pathways. These two forms of the ubiquitin signal contribute to three different pathways related to the maintenance of genome integrity that are responsible for the processing of DNA double-strand breaks, the repair of interstrand cross links and the bypass of lesions during DNA replication.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Repair; DNA Replication; Humans; Models, Biological; Models, Genetic; Signal Transduction; Ubiquitin
PubMed: 20551964
DOI: 10.1038/nrm2921 -
Cell Research Jan 2008The history of the repair of damaged DNA can be traced to the mid-1930s. Since then multiple DNA repair mechanisms, as well as other biological responses to DNA damage,... (Review)
Review
The history of the repair of damaged DNA can be traced to the mid-1930s. Since then multiple DNA repair mechanisms, as well as other biological responses to DNA damage, have been discovered and their regulation has been studied. This article briefly recounts the early history of this field.
Topics: Animals; DNA Damage; DNA Repair; Deoxyribodipyrimidine Photo-Lyase; Genetic Predisposition to Disease; Humans; Mutagenesis; Neoplasms
PubMed: 18157159
DOI: 10.1038/cr.2007.113 -
Antioxidants & Redox Signaling May 2011Stroke is a common cause of death and serious long-term adult disability. Oxidative DNA damage is a severe consequence of oxidative stress associated with ischemic... (Review)
Review
Stroke is a common cause of death and serious long-term adult disability. Oxidative DNA damage is a severe consequence of oxidative stress associated with ischemic stroke. The accumulation of DNA lesions, including oxidative base modifications and strand breaks, triggers cell death in neurons and other vulnerable cell populations in the ischemic brain. DNA repair systems, particularly base excision repair, are endogenous defense mechanisms that combat oxidative DNA damage. The capacity for DNA repair may affect the susceptibility of neurons to ischemic stress and influence the pathological outcome of stroke. This article reviews the accumulated understanding of molecular pathways by which oxidative DNA damage is triggered and repaired in ischemic cells, and the potential impact of these pathways on ischemic neuronal cell death/survival. Genetic or pharmacological strategies that target the signaling molecules in DNA repair responses are promising for potential clinically effective treatment. Further understanding of mechanisms for oxidative DNA damage and its repair processes may lead to new avenues for stroke management.
Topics: Animals; Brain Ischemia; DNA Damage; DNA Repair; Humans; Models, Biological; Signal Transduction
PubMed: 20677909
DOI: 10.1089/ars.2010.3451 -
Radiation Research Jul 2013The accumulated evidence in the literature indicates that a cluster of two or more lesions within one or two helical turns of the DNA is more challenging to repair than... (Review)
Review
The accumulated evidence in the literature indicates that a cluster of two or more lesions within one or two helical turns of the DNA is more challenging to repair than individual, widely dispersed lesions. The biological importance of clustered DNA lesions, especially complex double-strand breaks (DSB) and some types of non-DSB clusters (e.g., opposed bases that are oxidized), are now well known within the radiation research community. Still, many details of the induction and biological processing of complex clusters remain to be elucidated, especially in human cells. In this mini-review, we discuss recent advances in our understanding of the pathway(s) used by the mammalian cells to process and efficiently repair complex clusters other than the DSB. The effects of radiation quality and hypoxia on cluster induction and complexity are also briefly reviewed and discussed. Additional research is needed to better understand and quantify the multi-scale physiochemical and biological processes ultimately responsible for radiation-induced mutagenesis and genomic instability. New information and models to better quantify intermediate events (outcomes) related to the biological processing of non-DSB clusters are also important for ongoing efforts to assess the human health risks of terrestrial and space radiation environments and to guide the radiation therapy treatment planning process, especially for protons and carbon ions.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Humans; Oxidation-Reduction; Radiation, Ionizing; Radiotherapy
PubMed: 23682596
DOI: 10.1667/RR3041.1 -
Environmental and Molecular Mutagenesis Jul 2010DNA interstrand crosslinks (ICLs) are induced by a number of bifunctional antitumor drugs such as cisplatin, mitomycin C, or the nitrogen mustards as well as endogenous... (Review)
Review
DNA interstrand crosslinks (ICLs) are induced by a number of bifunctional antitumor drugs such as cisplatin, mitomycin C, or the nitrogen mustards as well as endogenous agents formed by lipid peroxidation. The repair of ICLs requires the coordinated interplay of a number of genome maintenance pathways, leading to the removal of ICLs through at least two distinct mechanisms. The major pathway of ICL repair is dependent on replication, homologous recombination, and the Fanconi anemia (FA) pathway, whereas a minor, G0/G1-specific and recombination-independent pathway depends on nucleotide excision repair. A central step in both pathways in vertebrates is translesion synthesis (TLS) and mutants in the TLS polymerases Rev1 and Pol zeta are exquisitely sensitive to crosslinking agents. Here, we review the involvement of Rev1 and Pol zeta as well as additional TLS polymerases, in particular, Pol eta, Pol kappa, Pol iota, and Pol nu, in ICL repair. Biochemical studies suggest that multiple TLS polymerases have the ability to bypass ICLs and that the extent ofbypass depends upon the structure as well as the extent of endo- or exonucleolytic processing of the ICL. As has been observed for lesions that affect only one strand of DNA, TLS polymerases are recruited by ubiquitinated proliferating nuclear antigen (PCNA) to repair ICLs in the G0/G1 pathway. By contrast, this data suggest that a different mechanism involving the FA pathway is operative in coordinating TLS in the context of replication-dependent ICL repair.
Topics: Animals; Cross-Linking Reagents; DNA; DNA Repair; DNA-Directed DNA Polymerase; Humans; Models, Molecular
PubMed: 20658647
DOI: 10.1002/em.20573 -
Mechanisms of Ageing and Development Jul 2017The presence of damaged and microbial DNA can pose a threat to the survival of organisms. Cells express various sensors that recognize specific aspects of such... (Review)
Review
The presence of damaged and microbial DNA can pose a threat to the survival of organisms. Cells express various sensors that recognize specific aspects of such potentially dangerous DNA. Recognition of damaged or microbial DNA by sensors induces cellular processes that are important for DNA repair and inflammation. Here, we review recent evidence that the cellular response to DNA damage and microbial DNA are tightly intertwined. We also discuss insights into the parameters that enable DNA sensors to distinguish damaged and microbial DNA from DNA present in healthy cells.
Topics: Animals; Bacteria; DNA Repair; DNA, Bacterial; Humans; Inflammation
PubMed: 27614000
DOI: 10.1016/j.mad.2016.09.001 -
Reviews of Physiology, Biochemistry and... 1996
Review
Topics: Animals; Apoptosis; DNA Damage; DNA Repair; Genes, p53; Humans; Mutation; Tumor Suppressor Protein p53
PubMed: 8533012
DOI: 10.1007/BFb0048265 -
Seminars in Radiation Oncology Oct 2001Cellular responses to ionizing radiation (IR) include (a) activation of signal transduction enzymes; (b) stimulation of DNA repair, most notably DNA double strand break... (Review)
Review
Cellular responses to ionizing radiation (IR) include (a) activation of signal transduction enzymes; (b) stimulation of DNA repair, most notably DNA double strand break (DSB) repair by homologous or nonhomologous recombinatorial pathways; (c) activation of transcription factors and subsequent IR-inducible transcript and protein changes; (d) cell cycle checkpoint delays in G(1), S, and G(2) required for repair or for programmed cell death of severely damaged cells; (e) activation of zymogens needed for programmed cell death (although IR is a poor inducer of such responses in epithelial cells); and (f) stimulation of IR-inducible proteins that may mediate bystander effects influencing signal transduction, DNA repair, angiogenesis, the immune response, late responses to IR, and possibly adaptive survival responses. The overall response to IR depends on the cell's inherent genetic background, as well as its ability to biochemically and genetically respond to IR-induced damage. To improve the anti-tumor efficacy of IR, our knowledge of these pleiotropic responses must improve. The most important process for the survival of a tumor cell following IR is the repair of DNA double strand breaks (DSBs). Using yeast two-hybrid analyses along with other molecular and cellular biology techniques, we cloned transcripts/proteins that are involved in, or presumably affect, nonhomologous DNA double strand break end-joining (NHEJ) repair mediated by the DNA-PK complex. Using Ku70 as bait, we isolated a number of Ku-binding proteins (KUBs). We identified the first X-ray-inducible transcript/protein (xip8, Clusterin (CLU)) that associates with DNA-PK. A nuclear form of CLU (nCLU) prevented DNA-PK-mediated end joining, and stimulated cell death in response to IR or when overexpressed in the absence of IR. Structure-function analyses using molecular and cellular (including green fluorescence-tagged protein trafficking) biology techniques showed that nCLU appears to be an inactive protein residing in the cytoplasm of epithelial cells. Following IR injury, nCLU levels increase and an as yet undefined posttranslational modification appears to alter the protein, exposing nuclear localization sequences (NLSs) and coiled-coil domains. The modified protein translocates to the nucleus and triggers cell death, presumably through its interaction specifically with Ku70. Understanding nCLU responses, as well as the functions of the KUBs, will be important for understanding DSB repair. Knowledge of DSB repair may be used to improve the antitumor efficacy of IR, as well as other chemotherapeutic agents.
Topics: Cell Survival; DNA Damage; DNA Repair; DNA, Neoplasm; Humans; Neoplasm Proteins; Neoplasms; Radiation, Ionizing; Signal Transduction
PubMed: 11677660
DOI: 10.1053/srao.2001.26912