Uv-induced Dna Damage And Repair A Review Pdf Writers
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Cells respond to DNA damage by activating checkpoint signaling and DNA repair pathways, collectively termed the DNA damage response DDR , which promotes cell survival, and suppresses cancer by promoting genome stability and by triggering programmed cell death pathways. The DDR is a major determinant of cancer cell responses to chemo- and radiotherapy, most of which cause DNA damage directly or indirectly, thus DDR components are enticing targets in the quest to augment cancer therapy 1 - 6.
- Translational research in radiation-induced DNA damage signaling and repair
- A brief history of the DNA repair field
- The Dark Side of UV-Induced DNA Lesion Repair
- Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies
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Translational research in radiation-induced DNA damage signaling and repair
Halophilic archaea push the limits of life at several extremes. In particular, they are noted for their biochemical strategies in dealing with osmotic stress, low water activity and cycles of desiccation in their hypersaline environments.
Another feature common to their habitats is intense ultraviolet UV radiation, which is a challenge that microorganisms must overcome. The consequences of high UV exposure include DNA lesions arising directly from bond rearrangement of adjacent bipyrimidines, or indirectly from oxidative damage, which may ultimately result in mutation and cell death. As such, these microorganisms have evolved a number of strategies to navigate the threat of DNA damage, which we differentiate into two categories: DNA repair and photoprotection.
Photolesions that do arise are addressed by a number of DNA repair mechanisms that halophilic archaea efficiently utilize, which include photoreactivation, nucleotide excision repair, base excision repair, and homologous recombination. This review seeks to place DNA damage, repair, and photoprotection in the context of halophilic archaea and the solar radiation of their hypersaline environments.
We also provide new insight into the breadth of strategies and how they may work together to produce remarkable UV-resistance for these microorganisms. Halophilic archaea are the predominant residents of hypersaline extreme environments, taxonomically classified within the family Halobacteriaceae , order Halobacteriales.
Most require high salinity for survival or growth from 2 M to upward of 5 M NaCl at saturation and lyse in water that is lower in ionic strength Oren, Remarkably, they can live in the salt-saturated fluid inclusions of salt crystals e. The salt lakes, ponds, and deposits inhabited by these microorganisms present challenges in addition to high salinity, one being high exposure to solar UV radiation that which reaches Earth is divided by wavelength range into UV-A, to nm, and UV-B, to nm.
Does the salt in the brine environment impact the exposure of halophilic archaea to UV-induced DNA damage by increasing light penetration?
It is clear that at least UV-A radiation penetrates more deeply in saline water Huovinen et al. Also, salt in and around such lakes causes mobilization of atmospheric chlorine, which has depleted ozone concentrations, leading to more UV exposure Stutz et al. Therefore, halophilic archaea may experience a significant dose of UV light in their native environments. However, halophilic archaea in desiccated salty shores or evaporite formations Figure 1a may receive less UV exposure.
In the lab, such microorganisms inhabiting salt crystal fluid inclusions received some protection from ultraviolet light radiation Fendrihan et al.
Carotenoid pigmentation in Great Salt Lake Utah, United States halophilic archaea a embedded in a shoreline salt crust, b growing in colonies on salt agar, and c coloring the north arm water pink.
While not photosynthetic, halophilic archaea are facultative phototrophic organisms Bryant and Frigaard, , and their growth is enhanced when cultured in the light Oren, Some species possess light-driven proton pumps, bacteriorhodopsins, that can drive ATP synthesis e. Halophilic archaea may have more than one rhodopsin; for example, Haloarcula marismortui has six homologous rhodopsin genes Baliga et al. The energetic benefits ATP synthesis of phototropism necessitate routine exposure to sunlight, resulting in high levels of UV radiation.
Exposure to visible light also regulates genes for the formation of gas vesicles Englert et al. Excessive exposure to sunlight in their environment has likely contributed to the evolution of other photobiology for halophilic archaea. For example, these microorganisms display remarkable UV resistance, first noted by Dundas and Larsen This observation is well-supported by more recent studies; for example, Shahmohammadi et al. Clearly, halophilic archaea have strategies for surviving and thriving in high UV radiation despite the threats of cellular and DNA damage.
UV-B, especially, affects both cellular proteins and DNA since these molecules absorb in this wavelength range; however, this review will focus only on DNA. Halophilic archaea live in high salinity environments with excessive UV exposure and desiccating conditions. This occurs most notably through the induction of cyclobutane pyrimidine dimers CPDs , pyrimidine pyrimidone photoproducts [ PPs], and the PP-related Dewar valence isomers Figure 2 Yoon et al.
Indeed, Moeller et al. Shown above are TT photolesions. Figure adapted from Rastogi et al. CPDs are the predominating photoproduct Besaratinia et al. Flanking sequences are also implicated in influencing CPD vs. Perdiz et al. These may be produced by absorption of UV-A or UV-B photons by, and subsequent activation of, endogenous photosensitizers such as porphyrins and flavins.
Resulting specific DNA damage is shown in the final column. Photooxidative DNA damage includes base modifications and strand breaks and occurs through one of two mechanisms Figure 3. The type II major mechanism induces guanine modification, and is mediated by singlet oxygen 1 O 2 generated by an energy transfer from an excited photosensitizer to molecular oxygen Kawanishi and Hiraku, The consequence of DNA lesions, for any organism, is ultimately mutation or even cell death.
When the helix undergoes DNA replication, damaged bases may result in mispairing or replication blocks, leading to mutation or partially replicated genomes reviewed in Friedberg, The impact of UV-induced DNA damage on the mutation rate is moderated by photoprotective mechanisms that prevent damage, and perhaps most importantly, DNA repair processes that fix it.
Halophilic archaea use both of these strategies, which are explored below. Halophilic archaea have robust and efficient systems for repairing different types of damage reviewed in Kish and DiRuggiero, and possess genes that share lineages with both eukaryotic cells e. Baliga and others used a systems approach to identify repair systems in the lab model, H. This study not only identified genes in dark and light see below DNA repair pathways, but also discovered several enzymes involved in oxidative repair.
Indeed, halophilic archaea appear to have an arsenal of machines that mitigate the DNA damaging effects of UV exposure Table 1. TABLE 1. A photolyase enzyme recognizes a lesion, binds to the site, and from there it is a single-step chemical process that uses blue to near-UV light energy to return the CPD or PP to its original state Sancar, The catalytic cycle of photolyases rely on a non-covalently bound cofactor, flavin adenine dinucleotide FAD reviewed in Weber, Both the ground-state redox properties and the excited-state properties of the FAD cofactor are utilized.
All photolyases are homologous across bacteria, archaea and eukaryotes, which suggests this mechanism developed early in evolution Eisen and Hanawalt, Photoreactivation genes, phr1 and phr2 , that encode photolyase enzymes have been described in several studies on halophilic archaea DasSarma et al. Interestingly, in gene knockout studies of phr1 and phr2 , only phr2 was associated with PHR in H. There may also be species-specific regulation Kish and DiRuggiero, since UV irradiation induced transcription of the ph2 gene in Halococcus hamelinensis Leuko et al.
The function of phr1 is unclear. Kanai et al. A study on the evolution of photolyase genes also demonstrates that specificity for CPD vs. Its machinery does not require light for the reactions to occur. There are several proteins involved that carry out this multi-step process involving recognition of the DNA damage e. A DNA polymerase must then build a new strand complementary to the undamaged one, and finally, ligase seals the phosphodiester backbone.
Halophilic archaea species may have eukaryotic homolog NER genes as well as the bacterial UvrABCD system, as homologs from both the XP system mammalian and Rad system yeast have been described in the archaea domain Eisen and Hanawalt, For example, H. Despite the observation of eukaryotic repair genes, at least the lab model species H. It has been theorized that other genes may be involved in repair-supportive processes such as addressing damage causing stalled replication forks Boubriak et al.
An early investigation of H. To date, a number of halophilic archaea species have been shown to use NER to repair photodamage, including H. Furthermore, H. Stantial et al. A uvrA dependence was observed in H. DNA glycosylases that are specific to the particular photooxidative damage cleave the N -glycosidic bond between the base and the deoxyribose ring. The DNA backbone is then cleaved by an abasic-site endonuclease and the deoxyribose sugar is removed.
The opposite strand provides the template for a repair polymerase to replace the removed nucleotide, and ligase seals the backbone. These are found across the halophilic archaea with some exceptions and variations Capes et al. Notably, alkA is missing from Haloquadratum walsbyi , and the nthA gene has three variants in some species. Other genes involved in this repair pathway are also present, indicating halophilic archaea have a fully functional BER apparatus.
Upon UV-irradiation, Baliga et al. In bacteria, the majority of these are breaks in the backbone and are repaired by ligase, but damage that creates an apurinic or apyrimidinic site is repaired by BER e.
The RecA protein brings homologous molecules together and facilitates this strand exchange. Recombinational repair can result in mutation as it has the potential to cause genome rearrangements. In bacteria e. The eukaryotic Rad51 family of proteins e. Also, halophilic archaea have homologs to the yeast proteins Mre11, an HR nuclease, and Rad50, an HR ATPase, suggesting that the archaeal systems are likely similar in complexity to the eukaryotic yeast model Woods and Dyall-Smith, When a radA mutant of H.
In wild type H. Also, in this strain, mutant studies show mre11 is likely involved in DSB end processing as in eukaryotes, but not rad50 Kish and DiRuggiero, , and double mutants of these genes in H. Halophilic archaea are polyploid Breuert et al. However, polyploidy may also give the cells more correct sequence templates from which to draw in repairing the damaged area Kish and DiRuggiero, ; Kish and DiRuggiero, When looking at UV-induced gene induction in H. To date, the SOS response is thought to be absent in halophilic archaea.
These photoprotective systems are thought to prevent damage before it occurs, thereby reducing the impact on, or even photodamage to, the DNA repair machinery. The red-orange and pink colors characteristic of aquatic hypersaline ecosystems such as Great Salt Lake, Utah are attributed to the accumulation of carotenoid pigments within cell membranes of resident halophilic archaea Figure 1.
Though not the subject of this review, we should note that there are also halophilic, carotenoid-containing bacteria, such as the Salinbacter genus, present in lower abundance. These compounds are comprised of long, conjugated hydrocarbon chains that generally possess oxygen-containing functional groups and symmetry about the central carbon Figure 4. Halophilic archaea are distinguished by a unique set of carotenoids Kelly et al.
Two of these molecules are joined to form phytoene, which is subsequently converted to lycopene through stepwise desaturation Kushwaha et al. Other retinal-containing, light-energy transducing proteins are found in H.
A brief history of the DNA repair field
Metrics details. UV-induced damage can induce apoptosis or trigger DNA repair mechanisms. Minor DNA damage is thought to halt the cell cycle to allow effective repair, while more severe damage can induce an apoptotic program. In addition, pTpT, a molecular mimic of CPD was tested in vitro and in vivo for the ability to induce cell death and cell cycle alterations. Apoptosis was monitored 24 hours later by flow cytometric analysis of DNA content, using sub-G1 staining to indicate apoptotic cells. To confirm the effects observed with CPD lesions, the molecular mimic of CPD, pTpT, was also tested in vitro and in vivo for its effect on cell cycle and apoptosis. The specific repair of PP lesions after UVB exposure resulted in a dramatic reduction in apoptosis.
The protective ozone layer is continually depleting due to the release of deteriorating environmental pollutants. The diminished ozone layer contributes to excessive exposure of cells to ultraviolet UV radiation. This leads to various cellular responses utilized to restore the homeostasis of exposed cells. DNA is the primary chromophore of the cells that absorbs sunlight energy. Exposure of genomic DNA to UV light leads to the formation of multitude of types of damage depending on wavelength and exposure time that are removed by effectively working repair pathways. The aim of this review is to summarize current knowledge considering cellular response to UV radiation with special focus on DNA damage and repair and to give a comprehensive insight for new researchers in this field. We also highlight most important future prospects considering application of the progressing knowledge of UV response for the clinical control of diverse pathologies.
PDF | The protective ozone layer is continually depleting due to the release of Authors: Mateusz Kciuk at University of Lodz. Mateusz Kciuk Review. Focus on UV-Induced DNA Damage and. Repair—Disease Relevance.
The Dark Side of UV-Induced DNA Lesion Repair
In their life cycle, plants are exposed to various unfavorable environmental factors including ultraviolet UV radiation emitted by the Sun. UV-A and UV-B, which are partially absorbed by the ozone layer, reach the surface of the Earth causing harmful effects among the others on plant genetic material. Some examples of DNA damage induced by UV are pyrimidine dimers, oxidized nucleotides as well as single and double-strand breaks.
Halophilic archaea push the limits of life at several extremes. In particular, they are noted for their biochemical strategies in dealing with osmotic stress, low water activity and cycles of desiccation in their hypersaline environments. Another feature common to their habitats is intense ultraviolet UV radiation, which is a challenge that microorganisms must overcome. The consequences of high UV exposure include DNA lesions arising directly from bond rearrangement of adjacent bipyrimidines, or indirectly from oxidative damage, which may ultimately result in mutation and cell death. As such, these microorganisms have evolved a number of strategies to navigate the threat of DNA damage, which we differentiate into two categories: DNA repair and photoprotection.
Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies
Rajesh P. Tyagi, Rajeshwar P. DNA is one of the prime molecules, and its stability is of utmost importance for proper functioning and existence of all living systems. Genotoxic chemicals and radiations exert adverse effects on genome stability. To counteract these lesions, organisms have developed a number of highly conserved repair mechanisms such as photoreactivation, base excision repair BER , nucleotide excision repair NER , and mismatch repair MMR. Additionally, double-strand break repair by homologous recombination and nonhomologous end joining , SOS response, cell-cycle checkpoints, and programmed cell death apoptosis are also operative in various organisms with the expense of specific gene products. This review deals with UV-induced alterations in DNA and its maintenance by various repair mechanisms.
We corrected the fact that the laser we used is not UV but nm, and clarified that this type of experiment only allows one to measure local increases in protein concentration, and not protein binding to the site of damage or protein movement. We state that we use higher laser power than used in most studies in order to demonstrate the photoconversion effect and cite a study in which photoconversion was detected and the experimental setup was adjusted accordingly. We suggest that sensitizing DNA by Hoechst in order to influence the type of damage can be replaced by altering the laser source.
DNA damage can be induced by various endogenous and exogenous agents. Upon detection of damage, the DNA damage response DDR is immediately elicited to regain genomic integrity via chromatin remodeling, signaling transduction and amplification Ciccia and Elledge, Simultaneously, various histone-modifying enzymes, heterochromatin factors and ATP-dependent chromatin remodelers work cooperatively to relax the chromatin structure and ensure that additional repair factors have access to the DSBs Price and D'Andrea, Despite all these advances in understanding the DDR, how DSBs are initially and precisely recognized is largely unknown. Seven sirtuins SIRT with various enzymatic activities and physiological functions are expressed in mammals. Despite their rapid mobilization to DNA breaks, the triggers for sirtuin recruitment are obscure Vazquez et al.
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