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Molecules (Basel, Switzerland) Sep 2022The photolyase family consists of flavoproteins with enzyme activity able to repair ultraviolet light radiation damage by photoreactivation. DNA damage by the formation... (Review)
Review
The photolyase family consists of flavoproteins with enzyme activity able to repair ultraviolet light radiation damage by photoreactivation. DNA damage by the formation of a cyclobutane pyrimidine dimer (CPD) and a pyrimidine-pyrimidone (6-4) photoproduct can lead to multiple affections such as cellular apoptosis and mutagenesis that can evolve into skin cancer. The development of integrated applications to prevent the negative effects of prolonged sunlight exposure, usually during outdoor activities, is imperative. This study presents the functions, characteristics, and types of photolyases, their therapeutic and cosmetic applications, and additionally explores some photolyase-producing microorganisms and drug delivery systems.
Topics: DNA Repair; Deoxyribodipyrimidine Photo-Lyase; Flavoproteins; Pyrimidine Dimers; Pyrimidines; Pyrimidinones; Ultraviolet Rays
PubMed: 36144740
DOI: 10.3390/molecules27185998 -
Genes Jul 2021The nucleotide excision repair (NER) is essential for the repair of ultraviolet (UV)-induced DNA damage, such as cyclobutane pyrimidine dimers (CPDs) and... (Review)
Review
The nucleotide excision repair (NER) is essential for the repair of ultraviolet (UV)-induced DNA damage, such as cyclobutane pyrimidine dimers (CPDs) and 6,4-pyrimidine-pyrimidone dimers (6,4-PPs). Alterations in genes of the NER can lead to DNA damage repair disorders such as Xeroderma pigmentosum (XP). XP is a rare autosomal recessive genetic disorder associated with UV-sensitivity and early onset of skin cancer. Recently, extensive research has been conducted on the functional relevance of splice variants and their relation to cancer. Here, we focus on the functional relevance of alternative splice variants of XP genes.
Topics: DNA Damage; DNA Repair; Humans; Mutation; Pyrimidine Dimers; RNA Splicing; Xeroderma Pigmentosum
PubMed: 34440347
DOI: 10.3390/genes12081173 -
Photochemistry and Photobiology Sep 2022The dominant DNA damage generated by UV exposure is the cyclobutane pyrimidine dimer (CPD), which alters skin cell physiology and induces cell death and mutation....
The dominant DNA damage generated by UV exposure is the cyclobutane pyrimidine dimer (CPD), which alters skin cell physiology and induces cell death and mutation. Genome-wide nucleotide-resolution analysis of CPDs in melanocytes and fibroblasts has identified "CPD hyperhotspots", pyrimidine-pyrimidine sites hundreds of fold more susceptible to the generation of CPDs than the genomic average. Identifying hyperhotspots in keratinocytes could enable measuring individual past UV exposure in small skin samples and predicting future skin cancer risk. We therefore exposed neonatal human epidermal keratinocytes to narrowband UVB and quantified CPDs using the adductSeq high-throughput DNA sequencing method. Keratinocytes contained thousands of CPD hyperhotspots, with a UVB-sensitivity up to 550 fold greater than the genomic average. As with melanocytes, the most sensitive sites were located in promoter regions at ETS-family transcription factor binding sequence motifs, near RNA processing genes. Moreover, they lay at sequence motifs bound to ETS1 in CpG islands. These genes were specifically upregulated in skin and the CPD hyperhotspots were mutated in a fraction of keratinocyte cancers. Crucially for their biological importance and practical application, CPD hyperhotspot locations and UV-sensitivity ranking demonstrated high reproducibility across experiments and across skin donors. CPD hyperhotspots are therefore sensitive indicators of UV exposure.
Topics: DNA Damage; Humans; Infant, Newborn; Keratinocytes; Pyrimidine Dimers; Reproducibility of Results; Transcription Factors; Ultraviolet Rays
PubMed: 35944237
DOI: 10.1111/php.13683 -
Photochemistry and Photobiology Mar 2023Light is one way to excite an electron in biology. Another is chemiexcitation, birthing a reaction product in an electronically excited state rather than exciting from... (Review)
Review
Light is one way to excite an electron in biology. Another is chemiexcitation, birthing a reaction product in an electronically excited state rather than exciting from the ground state. Chemiexcited molecules, as in bioluminescence, can release more energy than ATP. Excited states also allow bond rearrangements forbidden in ground states. Molecules with low-lying unoccupied orbitals, abundant in biology, are particularly susceptible. In mammals, chemiexcitation was discovered to transfer energy from excited melanin, neurotransmitters, or hormones to DNA, creating the lethal and carcinogenic cyclobutane pyrimidine dimer. That process was initiated by nitric oxide and superoxide, radicals triggered by ultraviolet light or inflammation. Several poorly understood chronic diseases share two properties: inflammation generates those radicals across the tissue, and cells that die are those containing melanin or neuromelanin. Chemiexcitation may therefore be a pathogenic event in noise- and drug-induced deafness, Parkinson's disease, and Alzheimer's; it may prevent macular degeneration early in life but turn pathogenic later. Beneficial evolutionary selection for excitable biomolecules may thus have conferred an Achilles heel. This review of recent findings on chemiexcitation in mammalian cells also describes the underlying physics, biochemistry, and potential pathogenesis, with the goal of making this interdisciplinary phenomenon accessible to researchers within each field.
Topics: Animals; Melanins; Photochemistry; Pyrimidine Dimers; Ultraviolet Rays; Mammals
PubMed: 36681894
DOI: 10.1111/php.13781 -
Physical Chemistry Chemical Physics :... May 2015Photolyases, a class of flavoproteins, use blue light to repair two types of ultraviolet-induced DNA damage, a cyclobutane pyrimidine dimer (CPD) and a... (Review)
Review
Photolyases, a class of flavoproteins, use blue light to repair two types of ultraviolet-induced DNA damage, a cyclobutane pyrimidine dimer (CPD) and a pyrimidine-pyrimidone (6-4) photoproduct (6-4PP). In this perspective, we review the recent progress in the repair dynamics and mechanisms of both types of DNA restoration by photolyases. We first report the spectroscopic characterization of flavin in various redox states and the active-site solvation dynamics in photolyases. We then systematically summarize the detailed repair dynamics of damaged DNA by photolyases and a biomimetic system through resolving all elementary steps on ultrafast timescales, including multiple intermolecular electron- and proton-transfer reactions and bond-breaking and -making processes. We determined the unique electron tunneling pathways, identified the key functional residues and revealed the molecular origin of high repair efficiency, and thus elucidate the molecular mechanisms and repair photocycles at the most fundamental level. We finally conclude that the active sites of photolyases, unlike the aqueous solution for the biomimetic system, provide a unique electrostatic environment and local flexibility and thus a dedicated synergy for all elementary dynamics to maximize the repair efficiency. This repair photomachine is the first enzyme that the entire functional evolution is completely mapped out in real time.
Topics: Animals; Catalytic Domain; DNA; DNA Damage; DNA Repair; Deoxyribodipyrimidine Photo-Lyase; Humans; Light; Models, Molecular; Mutation; Protein Conformation; Pyrimidine Dimers; Ultraviolet Rays
PubMed: 25870862
DOI: 10.1039/c4cp05286b -
Archives of Biochemistry and Biophysics Oct 2017Photolyase, a flavoenzyme containing flavin adenine dinucleotide (FAD) molecule as a catalytic cofactor, repairs UV-induced DNA damage of cyclobutane pyrimidine dimer... (Review)
Review
Photolyase, a flavoenzyme containing flavin adenine dinucleotide (FAD) molecule as a catalytic cofactor, repairs UV-induced DNA damage of cyclobutane pyrimidine dimer (CPD) and pyrimidine-pyrimidone (6-4) photoproduct using blue light. The FAD cofactor, conserved in the whole protein superfamily of photolyase/cryptochromes, adopts a unique folded configuration at the active site that plays a critical functional role in DNA repair. Here, we review our comprehensive characterization of the dynamics of flavin cofactor and its repair photocycles by different classes of photolyases on the most fundamental level. Using femtosecond spectroscopy and molecular biology, significant advances have recently been made to map out the entire dynamical evolution and determine actual timescales of all the catalytic processes in photolyases. The repair of CPD reveals seven electron-transfer (ET) reactions among ten elementary steps by a cyclic ET radical mechanism through bifurcating ET pathways, a direct tunneling route mediated by the intervening adenine and a two-step hopping path bridged by the intermediate adenine from the cofactor to damaged DNA, through the conserved folded flavin at the active site. The unified, bifurcated ET mechanism elucidates the molecular origin of various repair quantum yields of different photolyases from three life kingdoms. For 6-4 photoproduct repair, a similar cyclic ET mechanism operates and a new cyclic proton transfer with a conserved histidine residue at the active site of (6-4) photolyases is revealed.
Topics: Catalytic Domain; DNA Damage; DNA Repair; Deoxyribodipyrimidine Photo-Lyase; Electron Transport; Flavin-Adenine Dinucleotide; Flavoproteins; Protein Folding; Pyrimidine Dimers; Ultraviolet Rays
PubMed: 28802828
DOI: 10.1016/j.abb.2017.08.007 -
Photochemistry and Photobiology Jan 2017Photolyase, a photomachine discovered half a century ago for repair of sun-induced DNA damage of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone... (Review)
Review
Photolyase, a photomachine discovered half a century ago for repair of sun-induced DNA damage of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), has been characterized extensively in biochemistry (function), structure and dynamics since 1980s. The molecular mechanism and repair photocycle have been revealed at the most fundamental level. Using femtosecond spectroscopy, we have mapped out the entire dynamical evolution and determined all actual timescales of the catalytic processes. Here, we review our recent efforts in studies of the dynamics of DNA repair by photolyases. The repair of CPDs in three life kingdoms includes seven electron transfer (ET) reactions among 10 elementary steps through initial bifurcating ET pathways, a direct tunneling route and a two-step hopping path both through an intervening adenine from the cofactor to CPD, with a conserved folded structure at the active site. The repair of 6-4PPs is challenging and requires similar ET reactions and a new cyclic proton transfer with a conserved histidine residue at the active site of (6-4) photolyases. Finally, we also summarize our efforts on multiple intraprotein ET of photolyases in different redox states and such mechanistic studies are critical to the functional mechanism of homologous cryptochromes of blue-light photoreceptors.
Topics: Amino Acid Sequence; Catalytic Domain; DNA; DNA Damage; DNA Repair; Deoxyribodipyrimidine Photo-Lyase; Electron Transport; Energy Transfer; Oxidation-Reduction; Pyrimidine Dimers; Sequence Alignment; Sunlight
PubMed: 27991674
DOI: 10.1111/php.12695 -
Proceedings of the National Academy of... Feb 2021In this study, absorption, fluorescence, synchronous fluorescence, and Raman spectra of nonirradiated and ultraviolet (UV)-irradiated thymine solutions were recorded in...
In this study, absorption, fluorescence, synchronous fluorescence, and Raman spectra of nonirradiated and ultraviolet (UV)-irradiated thymine solutions were recorded in order to detect thymine dimer formation. The thymine dimer formation, as a function of irradiation dose, was determined by Raman spectroscopy. In addition, the formation of a mutagenic (6-4) photoproduct was identified by its synchronous fluorescence spectrum. Our spectroscopic data suggest that the rate of conversion of thymine to thymine dimer decreases after 20 min of UV irradiation, owing to the formation of an equilibrium between the thymine dimers and monomers. However, the formation of the (6-4) photoproduct continued to increase with UV irradiation. In addition, the Raman spectra of nonirradiated and irradiated calf thymus DNA were recorded, and the formation of thymine dimers was detected. The spectroscopic data presented make it possible to determine the mechanism of thymine dimer formation, which is known to be responsible for the inhibition of DNA replication that causes bacteria inactivation.
Topics: Animals; Cattle; DNA; DNA Damage; Pyrimidine Dimers; Spectrometry, Fluorescence; Spectrum Analysis, Raman; Thymine; Ultraviolet Rays
PubMed: 33526704
DOI: 10.1073/pnas.2025263118 -
DNA Repair Aug 2016Sunlight's ultraviolet wavelengths induce cyclobutane pyrimidine dimers (CPDs), which then cause mutations that lead to melanoma or to cancers of skin keratinocytes. In... (Review)
Review
Sunlight's ultraviolet wavelengths induce cyclobutane pyrimidine dimers (CPDs), which then cause mutations that lead to melanoma or to cancers of skin keratinocytes. In pigmented melanocytes, we found that CPDs arise both instantaneously and for hours after UV exposure ends. Remarkably, the CPDs arising in the dark originate by a novel pathway that resembles bioluminescence but does not end in light: First, UV activates the enzymes nitric oxide synthase (NOS) and NADPH oxidase (NOX), which generate the radicals nitric oxide (NO) and superoxide (O2(-)); these combine to form the powerful oxidant peroxynitrite (ONOO(-)). A fragment of the skin pigment melanin is then oxidized, exciting an electron to an energy level so high that it is rarely seen in biology. This process of chemically exciting electrons, termed "chemiexcitation", is used by fireflies to generate light but it had never been seen in mammalian cells. In melanocytes, the energy transfers radiationlessly to DNA, inducing CPDs. Chemiexcitation is a new source of genome instability, and it calls attention to endogenous mechanisms of genome maintenance that prevent electronic excitation or dissipate the energy of excited states. Chemiexcitation may also trigger pathogenesis in internal tissues because the same chemistry should arise wherever superoxide and nitric oxide arise near cells that contain melanin.
Topics: DNA Damage; Electrons; Humans; Keratinocytes; Melanins; Melanoma; NADPH Oxidases; Neoplasms, Radiation-Induced; Nitric Oxide; Nitric Oxide Synthase; Peroxynitrous Acid; Pyrimidine Dimers; Skin; Skin Neoplasms; Sunlight; Superoxides; Ultraviolet Rays
PubMed: 27262612
DOI: 10.1016/j.dnarep.2016.05.023 -
Genes Nov 2020Although solar light is indispensable for the functioning of plants, this environmental factor may also cause damage to living cells. Apart from the visible range,... (Review)
Review
Although solar light is indispensable for the functioning of plants, this environmental factor may also cause damage to living cells. Apart from the visible range, including wavelengths used in photosynthesis, the ultraviolet (UV) light present in solar irradiation reaches the Earth's surface. The high energy of UV causes damage to many cellular components, with DNA as one of the targets. Putting together the puzzle-like elements responsible for the repair of UV-induced DNA damage is of special importance in understanding how plants ensure the stability of their genomes between generations. In this review, we have presented the information on DNA damage produced under UV with a special focus on the pyrimidine dimers formed between the neighboring pyrimidines in a DNA strand. These dimers are highly mutagenic and cytotoxic, thus their repair is essential for the maintenance of suitable genetic information. In prokaryotic and eukaryotic cells, with the exception of placental mammals, this is achieved by means of highly efficient photorepair, dependent on blue/UVA light, which is performed by specialized enzymes known as photolyases. Photolyase properties, as well as their structure, specificity and action mechanism, have been briefly discussed in this paper. Additionally, the main gaps in our knowledge on the functioning of light repair in plant organelles, its regulation and its interaction between different DNA repair systems in plants have been highlighted.
Topics: Animals; DNA; DNA Damage; DNA Repair; Deoxyribodipyrimidine Photo-Lyase; Humans; Mutagenesis; Pyrimidine Dimers; Ultraviolet Rays
PubMed: 33158066
DOI: 10.3390/genes11111304