Ultraviolet Protection in the Cornea
Edit
This entry is adapted from the peer-reviewed paper 10.3390/biology11020278

Ultraviolet (UV) irradiation induces DNA lesions in all directly exposed tissues. In the human body, two tissues are chronically exposed to UV: the skin and the cornea. The most frequent UV-induced DNA lesions are cyclobutane pyrimidine dimers (CPDs) that can lead to apoptosis or induce tumorigenesis. Lacking the protective pigmentation of the skin, the transparent cornea is particularly dependent on nucleotide excision repair (NER) to remove UV-induced DNA lesions. The DNA damage response also triggers intracellular autophagy mechanisms to remove damaged material in the cornea. Therapeutic solutions involving xenogenic DNA-repair enzymes such as T4 endonuclease V or photolyases exist and are widely distributed for dermatological use. 

cornea UV autophagy

1. Cornea

The cornea is the superficial shield at the front of the eye. Its transparency is essential for the transmission of light into the eye and through to the retina, enabling visual perception. The cornea functions as a physical barrier, protecting the inner contents of the eye, while also providing a significant portion of the refraction needed for proper vision. The human cornea consists of five distinct layers. The anterior layer is the epithelium, and its underlying fibrous mesh is called the Bowman layer [1]. Posterior to the Bowman’s layer is the collagen-rich stroma, contributing to approximately 90% of the total corneal thickness. Beneath the stroma is Descemet’s membrane, which separates stroma from the most posterior corneal layer, the single cell layer endothelium (see Figure 1) [2][3].
Biology 11 00278 g001 550
Figure 1. Schematic cross-section of the tissue layers within the central cornea and the approximate shape of cell within the layers. The top cyan layer is the epithelium,;below it is the acellular Bowman layer. Below that in violet are the fibroblasts within the stroma. Below the stroma is the acellular Descemet’s membrane to which the monolayer of pink endothelial cells adhere. Epithelial (ED), Bowman layer (BL), Stroma (ST), Descemet’s membrane (DM), and Endothelial layer (EL).
It is currently thought that the limbus and its inhabiting cells maintain the border between the two different tissues, and that any damage to the limbus may enable an invasion of conjunctival cells into the cornea. This typically leads to vascularization and a loss in vision quality [4][5][6]. These disturbances may occur following UV damage where the limbal stem cells no longer maintain the border [7][8][9][10]. Although the role of epithelial factors in the maintenance of angiogenic and lymphangiogenic privilege seems evident, the role of the limbus as a physical barrier to vascular invasion seems poorly supported [11][12].
Damage to the epithelium must be repaired rapidly to restore barrier function and protect the cornea from bacteria or further trauma [13]. As the epithelial cell population is maintained by limbal stem cells (see Figure 2), the closure of wounds is severely impeded by any damage to their niche, the limbus [14]. The limbus can be considered a particularly critical component of the cornea as this perimeter of crypts is essential in maintaining a clear cornea fully covered in epithelium. While the limbus is vulnerable to threats ranging from viral and bacterial to chemical and traumatic, one particular source of stress is almost always present: UV radiation.
Biology 11 00278 g002 550
Figure 2. Limbal stem cells differentiating into migratory transient amplifying cells that migrate along the Bowman layer into the avascular central cornea to proliferate and terminally differentiate into functional epithelial cells. The limbal niche is maintained by proximity to blood vessels and secreted factors from stromal cells.

2. UV Effects on the Cornea

2.1. UV Damage and Repair Mechanisms

In the case of the cornea, acute UV exposure is known to cause photokeratitis, a painful inflammation where the epithelium, stroma, and endothelium may be affected and which leads to clouding [15][16][17][18]. Chronic UV exposure usually leads to long term conditions such as tumours (squamous cell carcinomas, malignant melanomas, lymphoma of the conjunctiva [19][20][21]) or keratopathy [22][23][24].

UV radiation entering the temporal limbus has been shown to focus at the nasal limbus, damaging limbal cells to a greater degree. This occurs specifically with UV entering at the temporal limbus that is then concentrated to the nasal limbus (see Figure 3) [25]. These damaged limbal cells and their descendants may then migrate from the limbus towards the center of the cornea [26].
Biology 11 00278 g003 550
Figure 3. UV light entering the cornea laterally at the temporal side of the cornea, becoming focused at the nasal side of the cornea. The increase in UV exposure at the nasal side is estimated to be of up to twenty times the exposure on the temporal side.

2.2. Pterygium Aetiology and Pathogenesis

One of the first clear definitions of pterygium describes a pterygos, a wing-shaped degenerative and hyperplastic process where the bulbar conjunctiva invades onto the cornea [27]. These vascularized, fibrotic degenerations continuously advance across the cornea over time [28]. It is well documented across several ethnicities, locations, and age-groups that the primary risk factor of pterygia is UV [29][30][31][32][33][34]. Pterygia are typically found at the interpalpebral zone of the cornea. Due to the peripheral light focusing effect, they will develop more often at nasal side and less often on the temporal side of the cornea [35].

2.3. UV-Induced DNA Lesion Formation

UV irradiation damages cellular DNA by causing the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) (see Figure 4) [36]. CPD and 6-4PP lesions are both results of neighbouring pyrimidine covalently binding to each other [37][38][39]. CPDs are the most frequent UV lesions and—when cells fail to induce cell death through the activation of the DNA damage response—lead to mutations that in turn promote malignancy [40][41][42]. Mutations amid CPDs are responsible for transition mutations via Cytosine and Thymine nucleotide dimerization [43][44].
Biology 11 00278 g004 550
Figure 4. Ultraviolet radiation causing cyclobutane pirymidine dimer and pyrimidine-pyrimidone (6-4) photoproduct formation in a DNA strand between two thymine bases. The two forms of DNA damage differ in the position of the bond created between the two bases.
Photolyases exist in organisms ranging from bacteria to plants and marsupials but are absent in placental mammals. Humans in fact lack CPD and 6-4PP photolyases and instead rely on nuclear excision repair (NER) pathway [45][46]. NER is far more versatile in removing a range of helix distorting lesions; however, they are far less effective to recognize CPD and 6-4PP lesions than the photolyases that have been selected to bind to only those lesions with high specificity. In contrast to the single enzyme photolyases, NER is executed by a highly complex mechanism involving dozens of proteins. While these proteins will not necessarily target UV damage specifically like the aforementioned photolyases, they are capable of repairing CPD and 6-4PP [47][48]. NER is initiated by lesion recognition by either the Xeroderma pigmentosum complementation group C (XPC) acting in concert with the RAD23 homolog B (RAD23B) as part of global genome (GG-) NER or by the Cockayne syndrome B (CSB) protein encoded by the excision repair cross complementation group 6 (ERCC6) gene as part of transcription-coupled (TC-) NER, dependent on the location of the damage. TC-NER and GG-NER differ in the way they recognise DNA damage. GG-NER relies on the XPC complex constantly probing the DNA for lesions while TC-NER relies on RNA polymerase stalling at lesion sites to recognize damaged DNA [49].
Both GG- and TC-NER recruit the NER core machinery including XPA and the TFIIH complex that unwind the double helix, verify the lesion, and subsequently recruit the ERCC1-XPF and the XPG endonucleases to excise a stretch containing the lesion [50]. Mutations in NER genes typically result in UV hypersensitivity of the skin and particularly when GG-NER is affected in a several thousand fold higher incidence of skin cancer in Xeroderma pigmentosum (XP) patients. In contrast, mutations affecting TC-NER result in Cockayne syndrome (CS) that is characterized by growth retardation and premature aging but not skin cancer. Distinct mutations in the TFIIH components XPD can lead to XP, rare combinations of XP and CS as well as trichothiodystrophy (TTD) that shares many features with CS but in addition leads to transcription elongation defects that cause brittle hair and nails [51][52]. These three diseases can also present eye-related anomalies such as conjunctivitis, photophobia, keratitis, pterygium, and corneal opacity [53], although these symptoms do not manifest in all patients.

2.4. The Role of Genotoxic Stress

The reason for the cornea’s greater resistance to UV lies in its ability to deal with genotoxic stress. Specifically, components of the genotoxic stress detection and response cascade such as DNA damage-binding protein 2 (DDB2), XPC, and tumour suppressor p53 are present in greater amounts in corneal epithelial cells than in epidermal keratinocyte [54]. The quantity of a protein within a cell is a result of the balance between production and degradation. In the corneal epithelial cells, the degradation of XPC, DDB2, and p53 is slowed such that the active forms of these proteins are more common [54]. While it seems like the cornea is better equipped than the skin to deal with UV damage, this could be interpreted as a compensation measure because the skin has corneocytes that form a physical barrier and prevent some genotoxic stress from occurring in the first place. The cornea instead relies on the tear film, which does not present as effective a barrier to UV [55][56].

2.5. Reactive Oxygen Species

UV may also damage epithelium by causing the formation of reactive oxygen species (ROS), free radicals that may oxidise cellular material such as proteins, organelles, or DNA [57]. When the amount of ROS in a cell exceeds the cellular antioxidant levels, damage will occur more readily and the cells may undergo apoptosis [58].

2.6. Disruption of Autophagy Mechanisms

Autophagy is a degradation mechanism that utilises the lysosome to remove proteins from the cell. This is done either as part of the natural turnover of proteins or as part of a stress response. The process is mediated by several regulators that transport the targeted proteins and control the rate at which the proteins are removed. This rate can be adjusted by several stimuli to remove damaged proteins. One of these stimuli is UV irradiation. Ataxia-telangiectasia mutated (ATM) and Rad3-related (ATR) are both damage sensors that can mediate the activation of p53 via checkpoint kinase 1 (CHK1) and checkpoint kinase 2 (CHK2). ATR may also activate the STK11/AMPK metabolic pathway to stimulate the tuberous sclerosis 2 (TSC2) tumor suppressor and regulate autophagy via Beclin 1 [59][60]. TSC1 and TSC2 may also downregulate mTOR activity [61]. The difference between ATM and ATR is that the former is an ATM-Chk2 pathway mostly activated by double-strand breaks, while the latter ATR/Chk1 is activated by single-strand breaks [62][63]. Both ATR and ATM inactivate mTORC1, enabling autophagy as a result [64].
UV has also been found to stabilize p53, enabling it to be one of the starting points of the cellular response to UV stress by greatly increasing the amount of p53 within the cell [65]. In enucleated cells, the inhibition of p53 leads to increased autophagy, indicating that the cytoplasmic p53 regulates autophagy [66].
Autophagy is a continuous process with several regulating factors. Following the initial formation of the early phagosome, The LC3 will begin separately to finalize the phagosome formation and allow it to be trafficked to initiate the process of lysosomal breakdown. This process involves the Atg10/Atg7-mediated process of Atg5-Atg12-Atg16 conjugation [67]. The sirtuin family has been documented as regulator of autophagy via this LC3 cascade [68]. It should be noted that the seven members of the sirtuin family respond to different stimuli and may even inhibit autophagy given the right circumstances [69].
While these autophagy mechanisms (see Figure 5) are thoroughly researched, their role in corneal damage repair and particularly their activation following UV damage, is poorly characterised. Autophagy modulating treatments such as resveratrol eye drops are already being researched to address several eye diseases [70][71][72][73], but their exact effect on corneal autophagy in not known. It had already been acknowledged that autophagy likely plays an important role in some UV-induced and UV-propagated diseases such as dry-eye disease and pterygium [74][75].
Biology 11 00278 g005 550
Figure 5. Simplified schematic representation of the autophagic cascade activated by UV damage of proteins.

2.7. Apoptosis

Apoptosis can be triggered by several factors such as cytokines, hormones, virus, or drugs. At the right concentrations, these stimuli lead to the activation of effector caspases that trigger the apoptotic program [76]. UV irradiation has been shown to cause the activation of ATP-sensitive potassium (K(ATP)) channels in affected cells causing a loss of K+ ions and a depolarization of the mitochondrial membrane [77][78]. Intracellular K+ is importantly linked with the inhibition of caspase, and K+ loss is linked with greater rates of apoptosis [79]. In the cornea specifically, it has been observed that while in vivo cells did not perish following exposure to background doses of UVB, cultured cells did perish when exposed to similar UVB doses [80]. It was found that tear film provided a high amount of K+ ions to the corneal epithelia, ensuring a degree of apoptosis-resistance to the chronically UV-irradiated epithelial cells [81]. This is in contrast with the skin which lacks this excess K+ and instead regularly sees UV-triggered apoptosis in the form of sunburn cells [82][83].

3. UV Pathogenesis and Rescue

The failure of DNA repair pathways, particularly NER, typically results in developmental disorders, neurological symptoms, and skin cancers. These conditions arise due to the inability of cells to repair DNA in populations of progenitor cells, noncycling cells, and UV-exposed cells [84]. While the disease itself is variable, one common trait unifies all of them: DNA photolesions are not being repaired.
The simplest method to prevent DNA photolesions is the avoidance of UV light, be it sunlight or artificial. 
Early work on the failure of UV defense system performed in plants found that a loss of CPD photolyase activity resulted in hypersensitivity to UVB [85]. CPD photolyase does not exist in placental mammals, [86]. There exist animal models with DNA repair mutations that involve the other NER proteins that target CPD and 6-4PP. A model of systemic ERCC1 deficiency showed polyploidy in the liver and kidney [87]. Polyploidy has been positively correlated to cell stress and senescence [88]. A mouse model of ERCC1-knockdown in the corneal endothelium of saw decreased cell density in the corneal endothelium [89]. Unfortunately, there are no reports of loss-of-function NER mutants specific to the corneal epithelia. Studies in humans looking at the NER expression profiles in Fuch’s endothelial corneal dystrophy (FECD) found that XPC was downregulated in patients that had FECD [90][91]. Although this does not make the cells more vulnerable to UV specifically, it does allow for faster accumulation of DNA lesions, which then lead to pathogenesis.
Because placental mammals lack CPD photolyase due to an evolutionary split, there has been some interest expressing CPD photolyase to potentially provide a much more competent repair enzyme. The photolyase in question is still expressed in marsupials and has been introduced into human cells harvested from an XP patient in an attempt to improve the rate of DNA repair. The marsupial photolyase functioned properly in the host cells and did improve survival of human cells following UV irradiation [92]. Similar experiments that used microinjections of purified photolyases from yeast also found that UV-mediated cell death was reduced, but to a lesser degree compared to the marsupial photolyase [93]. It was hypothesized that the yeast photolyase is not trafficked into the nucleus to the same degree as the marsupial photolyase. With such evidence, work continued with CPD photolyase introduction into placental mammals and a mouse line was generated that ubiquitously expressed either Potorous tridactylus CPD photolyase, Arabidopsis thaliana 6-4PP photolyase, or both [94][95]. The photoreactivation of CPD photolyase resulted in a markedly improved survival of UV-exposed cells in the mice, while photoreactivation of 6-4PPs did not noticeably affect UV-resistance. It should be noted that rodent cells have been documented multiple times as having CPD repair systems less effective than human CPD repair equivalents [96][97][98][99]. This lead to research on the introduction of CPD photolyase into mouse models and showed great improvement in recovery from UV damage [94][95].
Further work on repair of CPDs in human cells used an mRNA transfection system to express the marsupial Potorous tridactylus CPD photolyase in UVB-irradiated human epidermal keratinocytes. Results showed greatly reduced CPD amount and reduced activation of UV-induced cytokine such as IL-6 [100]. Use of this system also lead to the identification of which genes where more highly expressed in the presence of CPDs, and thus could be targeted by therapeutic approaches [101]. Cell cycle controllers like cyclin E1 and p15INK4b were expressed in greater quantities following JNK activation by UVB exposure. Several other genes were also identified with UV-dependent expression, although it is uncertain how beneficial the expression of each gene is [102]. Work on the UV-induced CPD-dependent and CPD-independent cellular mechanisms continues, with CPD photolyase as a major tool. The obvious potential of CPD photolyase as a therapeutic agent in humans has been applied, usually with skin in mind [103]. The potential of CPD photolyase in corneal healing comparatively sees less investigation, possibly due to the corneas greater success in dealing with CPDs with existing repair mechanisms or by simply changing the lifestyle of affected patients to better avoid UV exposure.

References

  1. DelMonte, D.W.; Kim, T. Anatomy and physiology of the cornea. J. Cataract Refract. Surg. 2011, 37, 588–598.
  2. Maurice, D.M. The structure and transparency of the cornea. J. Physiol. 1957, 136, 263–286.
  3. Schwarz, W.; Keyserlingk, D.G. On the fine structure of the human cornea with special reference to the problem of transparency. Z. Zellforsch Mikrosk. Anat. 1966, 73, 540–548.
  4. Kruse, F.E. Stem cells and corneal epithelial regeneration. Eye 1994, 8, 170–183.
  5. Zieske, J.D. Perpetuation of stem cells in the eye. Eye 1994, 8, 163–169.
  6. Yoon, J.J.; Ismail, S.; Sherwin, T. Limbal stem cells: Central concepts of corneal epithelial homeostasis. World J. Stem Cells 2014, 6, 391–403.
  7. Notara, M.; Behoudifard, S.; S. Kluth, M.A.; Masslo, C.; Ganss, C.; Frank, M.H.; Cursiefen, C. UV light-blocking contact lenses prevent UVB-induced DNA and oxidative damage of the limbal stem cell niche, protect against inflammation and maintain putative stem cell phenotype. Investig. Ophthalmol. Vis. Sci. 2019, 60, 920.
  8. Notara, M.; Refaian, N.; Brown, G.; Steven, P.; Bock, F.; Cursiefen, C. Effects of UVB irradiation on limbal stem cell niche and its role in cornea lymphangiogenesis. Investig. Ophthalmol. Vis. Sci. 2015, 56, 5622.
  9. Notara, M.; Refaian, N.; Braun, G.; Steven, P.; Bock, F.; Cursiefen, C. Short-Term Ultraviolet A Irradiation Leads to Dysfunction of the Limbal Niche Cells and an Antilymphangiogenic and Anti-inflammatory Micromilieu. Investig. Ophthalmol. Vis. Sci. 2016, 57, 928–939.
  10. Notara, M.; Braun, G.; Dreisow, M.L.; Bock, F.; Cursiefen, C. Avastin effects on human limbal epithelial cell function and phenotype in vitro. Investig. Ophthalmol. Vis. Sci. 2016, 57, 4343.
  11. Gao, X.; Guo, K.; Santosa, S.M.; Montana, M.; Yamakawa, M.; Hallak, J.A.; Han, K.Y.; Doh, S.J.; Rosenblatt, M.I.; Chang, J.H.; et al. Application of corneal injury models in dual fluorescent reporter transgenic mice to understand the roles of the cornea and limbus in angiogenic and lymphangiogenic privilege. Sci. Rep. 2019, 9, 12331.
  12. Azar, D.T. Corneal angiogenic privilege: Angiogenic and antiangiogenic factors in corneal avascularity, vasculogenesis, and wound healing (an American Ophthalmological Society thesis). Trans. Am. Ophthalmol. Soc. 2006, 104, 264–302.
  13. Klyce, S.D. 12 Endothelial pump and barrier function. Exp. Eye Res. 2020, 198, 108068.
  14. Ljubimov, A.V.; Saghizadeh, M. Progress in corneal wound healing. Prog. Retin. Eye Res. 2015, 49, 17–45.
  15. Kronschlager, M.; Talebizadeh, N.; Yu, Z.; Meyer, L.M.; Lofgren, S. Apoptosis in Rat Cornea After In Vivo Exposure to Ultraviolet Radiation at 300 nm. Cornea 2015, 34, 945–949.
  16. Miller, S. A focus on ultraviolet keratitis. Nursing 2009, 4, 12–16.
  17. Najjar, D.M.; Awwad, S.T.; Zein, W.M.; Haddad, W.F. Assessment of the corneal endothelium in acute ultraviolet keratitis. Med. Sci. Monit. 2006, 12, MT23–MT25.
  18. Willmann, G. Ultraviolet Keratitis: From the Pathophysiological Basis to Prevention and Clinical Management. High Alt. Med. Biol. 2015, 16, 277–282.
  19. Coroi, M.C.; Rosca, E.; Mutiu, G.; Coroi, T. Squamous carcinoma of the conjunctiva. Rom. J. Morphol. Embryol. 2011, 52 (Suppl. 1), 513–515.
  20. Olah, Z. Malignant tumor of the cornea and exroderma pigmentosum. Ceskoslovenska Oftalmol. 1968, 24, 119–122.
  21. Toshida, H.; Nakayasu, K.; Okisaka, S.; Kanai, A. Incidence of tumors and tumor-like lesions in the conjunctiva and the cornea. Nippon Ganka Gakkai Zasshi 1995, 99, 186–189.
  22. Newton, R.; Ferlay, J.; Reeves, G.; Beral, V.; Parkin, D.M. Effect of ambient solar ultraviolet radiation on incidence of squamous-cell carcinoma of the eye. Lancet 1996, 347, 1450–1451.
  23. Hatsusaka, N.; Yamamoto, N.; Miyashita, H.; Shibuya, E.; Mita, N.; Yamazaki, M.; Shibata, T.; Ishida, H.; Ukai, Y.; Kubo, E.; et al. Association among pterygium, cataracts, and cumulative ocular ultraviolet exposure: A cross-sectional study in Han people in China and Taiwan. PLoS ONE 2021, 16, e0253093.
  24. Sekelj, S.; Dekaris, I.; Kondza-Krstonijevic, E.; Gabric, N.; Predovic, J.; Mitrovic, S. Ultraviolet light and pterygium. Coll. Antropol. 2007, 31 (Suppl. 1), 45–47.
  25. Coroneo, M.T.; Muller-Stolzenburg, N.W.; Ho, A. Peripheral light focusing by the anterior eye and the ophthalmohelioses. Ophthalmic. Surg. 1991, 22, 705–711.
  26. Dushku, N.; Reid, T.W. Immunohistochemical evidence that human pterygia originate from an invasion of vimentin-expressing altered limbal epithelial basal cells. Curr. Eye Res. 1994, 13, 473–481.
  27. Hill, J.C.; Maske, R. Pathogenesis of pterygium. Eye 1989, 3, 218–226.
  28. Fonseca, E.C.; Rocha, E.M.; Arruda, G.V. Comparison among adjuvant treatments for primary pterygium: A network meta-analysis. Br. J. Ophthalmol. 2018, 102, 748–756.
  29. Lu, P.; Chen, X.; Kang, Y.; Ke, L.; Wei, X.; Zhang, W. Pterygium in Tibetans: A population-based study in China. Clin. Exp. Ophthalmol. 2007, 35, 828–833.
  30. Stevenson, L.J.; Mackey, D.A.; Lingham, G.; Burton, A.; Brown, H.; Huynh, E.; Tan, I.J.; Franchina, M.; Sanfilippo, P.G.; Yazar, S. Has the Sun Protection Campaign in Australia Reduced the Need for Pterygium Surgery Nationally? Ophthalmic. Epidemiol. 2021, 28, 105–113.
  31. Hirst, L.W.; Smith, J. Accuracy of diagnosis of pterygium by optometrists and general practitioners in Australia. Clin. Exp. Optom. 2020, 103, 197–200.
  32. Khanna, R.C.; Marmamula, S.; Cicinelli, M.V.; Mettla, A.L.; Giridhar, P.; Banerjee, S.; Shekhar, K.; Chakrabarti, S.; Murthy, G.V.S.; Gilbert, C.E.; et al. Fifteen-year incidence rate and risk factors of pterygium in the Southern Indian state of Andhra Pradesh. Br. J. Ophthalmol. 2021, 105, 619–624.
  33. Fang, X.L.; Chong, C.C.Y.; Thakur, S.; Da Soh, Z.; Teo, Z.L.; Majithia, S.; Lim, Z.W.; Rim, T.H.; Sabanayagam, C.; Wong, T.Y.; et al. Ethnic differences in the incidence of pterygium in a multi-ethnic Asian population: The Singapore Epidemiology of Eye Diseases Study. Sci. Rep. 2021, 11, 501.
  34. Rim, T.H.; Kang, M.J.; Choi, M.; Seo, K.Y.; Kim, S.S. The incidence and prevalence of pterygium in South Korea: A 10-year population-based Korean cohort study. PLoS ONE 2017, 12, e0171954.
  35. Kwok, L.S.; Kuznetsov, V.A.; Ho, A.; Coroneo, M.T. Prevention of the adverse photic effects of peripheral light-focusing using UV-blocking contact lenses. Investig. Ophthalmol. Vis. Sci. 2003, 44, 1501–1507.
  36. Sage, E. Distribution and repair of photolesions in DNA: Genetic consequences and the role of sequence context. Photochem. Photobiol. 1993, 57, 163–174.
  37. Rochette, P.J.; Bastien, N.; Todo, T.; Drouin, R. Pyrimidine (6-4) pyrimidone photoproduct mapping after sublethal UVC doses: Nucleotide resolution using terminal transferase-dependent PCR. Photochem. Photobiol. 2006, 82, 1370–1376.
  38. Liu, Z.; Tan, C.; Guo, X.; Kao, Y.T.; Li, J.; Wang, L.; Sancar, A.; Zhong, D. Dynamics and mechanism of cyclobutane pyrimidine dimer repair by DNA photolyase. Proc. Natl. Acad. Sci. USA 2011, 108, 14831–14836.
  39. Torizawa, T.; Ueda, T.; Kuramitsu, S.; Hitomi, K.; Todo, T.; Iwai, S.; Morikawa, K.; Shimada, I. Investigation of the cyclobutane pyrimidine dimer (CPD) photolyase DNA recognition mechanism by NMR analyses. J. Biol. Chem. 2004, 279, 32950–32956.
  40. Hutchinson, F. Induction of tandem-base change mutations. Mutat. Res. 1994, 309, 11–15.
  41. Yamada, D.; Dokainish, H.M.; Iwata, T.; Yamamoto, J.; Ishikawa, T.; Todo, T.; Iwai, S.; Getzoff, E.D.; Kitao, A.; Kandori, H. Functional Conversion of CPD and (6-4) Photolyases by Mutation. Biochemistry 2016, 55, 4173–4183.
  42. Mees, A.; Klar, T.; Gnau, P.; Hennecke, U.; Eker, A.P.; Carell, T.; Essen, L.O. Crystal structure of a photolyase bound to a CPD-like DNA lesion after in situ repair. Science 2004, 306, 1789–1793.
  43. McGregor, W.G.; Chen, R.H.; Lukash, L.; Maher, V.M.; McCormick, J.J. Cell cycle-dependent strand bias for UV-induced mutations in the transcribed strand of excision repair-proficient human fibroblasts but not in repair-deficient cells. Mol. Cell Biol. 1991, 11, 1927–1934.
  44. Steurer, B.; Turkyilmaz, Y.; van Toorn, M.; van Leeuwen, W.; Escudero-Ferruz, P.; Marteijn, J.A. Fluorescently-labelled CPD and 6-4PP photolyases: New tools for live-cell DNA damage quantification and laser-assisted repair. Nucleic Acids Res. 2019, 47, 3536–3549.
  45. Li, Y.F.; Kim, S.T.; Sancar, A. Evidence for lack of DNA photoreactivating enzyme in humans. Proc. Natl. Acad. Sci. USA 1993, 90, 4389–4393.
  46. van der Spek, P.J.; Kobayashi, K.; Bootsma, D.; Takao, M.; Eker, A.P.; Yasui, A. Cloning, tissue expression, and mapping of a human photolyase homolog with similarity to plant blue-light receptors. Genomics 1996, 37, 177–182.
  47. Munoz, M.J.; Nieto Moreno, N.; Giono, L.E.; Cambindo Botto, A.E.; Dujardin, G.; Bastianello, G.; Lavore, S.; Torres-Mendez, A.; Menck, C.F.M.; Blencowe, B.J.; et al. Major Roles for Pyrimidine Dimers, Nucleotide Excision Repair, and ATR in the Alternative Splicing Response to UV Irradiation. Cell Rep. 2017, 18, 2868–2879.
  48. Hsu, P.H.; Hanawalt, P.C.; Nouspikel, T. Nucleotide excision repair phenotype of human acute myeloid leukemia cell lines at various stages of differentiation. Mutat. Res.-Fund. Mol. Mech. Mutagenesis 2007, 614, 3–15.
  49. Marteijn, J.A.; Lans, H.; Vermeulen, W.; Hoeijmakers, J.H. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat. Rev. Mol. Cell Biol. 2014, 15, 465–481.
  50. Langie, S.A.; Wilms, L.C.; Hamalainen, S.; Kleinjans, J.C.; Godschalk, R.W.; van Schooten, F.J. Modulation of nucleotide excision repair in human lymphocytes by genetic and dietary factors. Br. J. Nutr. 2010, 103, 490–501.
  51. de Boer, J.; Hoeijmakers, J.H. Nucleotide excision repair and human syndromes. Carcinogenesis 2000, 21, 453–460.
  52. Vermeulen, W.; de Boer, J.; Citterio, E.; van Gool, A.J.; van der Horst, G.T.; Jaspers, N.G.; de Laat, W.L.; Sijbers, A.M.; van der Spek, P.J.; Sugasawa, K.; et al. Mammalian nucleotide excision repair and syndromes. Biochem. Soc. Trans. 1997, 25, 309–315.
  53. Rapin, I. Disorders of nucleotide excision repair. Handb. Clin. Neurol. 2013, 113, 1637–1650.
  54. Mallet, J.D.; Dorr, M.M.; Drigeard Desgarnier, M.C.; Bastien, N.; Gendron, S.P.; Rochette, P.J. Faster DNA Repair of Ultraviolet-Induced Cyclobutane Pyrimidine Dimers and Lower Sensitivity to Apoptosis in Human Corneal Epithelial Cells than in Epidermal Keratinocytes. PLoS ONE 2016, 11, e0162212.
  55. Mann, A.; Tighe, B. Contact lens interactions with the tear film. Exp. Eye Res. 2013, 117, 88–98.
  56. Wang, S.; Jiang, B.; Gu, Y. Changes of tear film function after pterygium operation. Ophthalmic. Res. 2011, 45, 210–215.
  57. Poljsak, B.; Dahmane, R. Free radicals and extrinsic skin aging. Dermatol. Res. Pract. 2012, 2012, 135206.
  58. de Jager, T.L.; Cockrell, A.E.; Du Plessis, S.S. Ultraviolet Light Induced Generation of Reactive Oxygen Species. Adv. Exp. Med. Biol. 2017, 996, 15–23.
  59. Wang, J.; Whiteman, M.W.; Lian, H.; Wang, G.; Singh, A.; Huang, D.; Denmark, T. A non-canonical MEK/ERK signaling pathway regulates autophagy via regulating Beclin 1. J. Biol. Chem. 2009, 284, 21412–21424.
  60. Alexander, A.; Cai, S.L.; Kim, J.; Nanez, A.; Sahin, M.; MacLean, K.H.; Inoki, K.; Guan, K.L.; Shen, J.; Person, M.D.; et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc. Natl. Acad. Sci. USA 2010, 107, 4153–4158.
  61. Feng, Z.; Zhang, H.; Levine, A.J.; Jin, S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl. Acad. Sci. USA 2005, 102, 8204–8209.
  62. Cimprich, K.A.; Cortez, D. ATR: An essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol. 2008, 9, 616–627.
  63. Smith, J.; Tho, L.M.; Xu, N.; Gillespie, D.A. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv. Cancer Res. 2010, 108, 73–112.
  64. Liu, M.; Zeng, T.; Zhang, X.; Liu, C.; Wu, Z.; Yao, L.; Xie, C.; Xia, H.; Lin, Q.; Xie, L.; et al. ATR/Chk1 signaling induces autophagy through sumoylated RhoB-mediated lysosomal translocation of TSC2 after DNA damage. Nat. Commun. 2018, 9, 4139.
  65. Maltzman, W.; Czyzyk, L. UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol. Cell Biol. 1984, 4, 1689–1694.
  66. Tasdemir, E.; Chiara Maiuri, M.; Morselli, E.; Criollo, A.; D’Amelio, M.; Djavaheri-Mergny, M.; Cecconi, F.; Tavernarakis, N.; Kroemer, G. A dual role of p53 in the control of autophagy. Autophagy 2008, 4, 810–814.
  67. Fujita, N.; Itoh, T.; Omori, H.; Fukuda, M.; Noda, T.; Yoshimori, T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol. Biol. Cell 2008, 19, 2092–2100.
  68. Zeng, R.; Chen, Y.; Zhao, S.; Cui, G.H. Autophagy counteracts apoptosis in human multiple myeloma cells exposed to oridonin in vitro via regulating intracellular ROS and SIRT1. Acta Pharmacol. Sin. 2012, 33, 91–100.
  69. Garva, R.; Thepmalee, C.; Yasamut, U.; Sudsaward, S.; Guazzelli, A.; Rajendran, R.; Tongmuang, N.; Khunchai, S.; Meysami, P.; Limjindaporn, T.; et al. Sirtuin Family Members Selectively Regulate Autophagy in Osteosarcoma and Mesothelioma Cells in Response to Cellular Stress. Front. Oncol. 2019, 9, 949.
  70. Shamsher, E.; Guo, L.; Davis, B.M.; Luong, V.; Ravindran, N.; Somavarapu, S.; Cordeiro, M.F. Resveratrol nanoparticles are neuroprotective in a rat model of glaucoma. Investig. Ophthalmol. Vis. Sci. 2021, 62, 2423.
  71. Abu-Amero, K.K.; Kondkar, A.A.; Chalam, K.V. Resveratrol and Ophthalmic Diseases. Nutrients 2016, 8, 200.
  72. Tsai, T.Y.; Chen, T.C.; Wang, I.J.; Yeh, C.Y.; Su, M.J.; Chen, R.H.; Tsai, T.H.; Hu, F.R. The Effect of Resveratrol on Protecting Corneal Epithelial Cells from Cytotoxicity Caused by Moxifloxacin and Benzalkonium Chloride. Investig. Ophthalmol. Vis. Sci. 2015, 56, 1575–1584.
  73. Ma, S.S.; Yu, Z.; Feng, S.F.; Chen, H.J.; Chen, H.Y.; Lu, X.H. Corneal autophagy and ocular surface inflammation: A new perspective in dry eye. Exp. Eye Res. 2019, 184, 126–134.
  74. Van Acker, S.I.; van den Bogerd, B.; Haagdorens, M.; Siozopoulou, V.; Dhubhghaill, S.N.; Pintelon, I.; Koppen, C. Pterygium-The Good, the Bad, and the Ugly. Cells 2021, 10, 1567.
  75. Martin, L.M.; Jeyabalan, N.; Tripathi, R.; Panigrahi, T.; Johnson, P.J.; Ghosh, A.; Mohan, R.R. Autophagy in corneal health and disease: A concise review. Ocul. Surf. 2019, 17, 186–197.
  76. Cao, C.; Healey, S.; Amaral, A.; Lee-Couture, A.; Wan, S.; Kouttab, N.; Chu, W.; Wan, Y. ATP-sensitive potassium channel: A novel target for protection against UV-induced human skin cell damage. J. Cell Physiol. 2007, 212, 252–263.
  77. Papucci, L.; Schiavone, N.; Witort, E.; Donnini, M.; Lapucci, A.; Tempestini, A.; Formigli, L.; Zecchi-Orlandini, S.; Orlandini, G.; Carella, G.; et al. Coenzyme q10 prevents apoptosis by inhibiting mitochondrial depolarization independently of its free radical scavenging property. J. Biol. Chem. 2003, 278, 28220–28228.
  78. Tang, J.Y.; Hwang, B.J.; Ford, J.M.; Hanawalt, P.C.; Chu, G. Xeroderma pigmentosum p48 gene enhances global genomic repair and suppresses UV-induced mutagenesis. Mol. Cell 2000, 5, 737–744.
  79. Hughes, F.M., Jr.; Bortner, C.D.; Purdy, G.D.; Cidlowski, J.A. Intracellular K+ suppresses the activation of apoptosis in lymphocytes. J. Biol. Chem. 1997, 272, 30567–30576.
  80. Singleton, K.R.; Will, D.S.; Schotanus, M.P.; Haarsma, L.D.; Koetje, L.R.; Bardolph, S.L.; Ubels, J.L. Elevated extracellular K+ inhibits apoptosis of corneal epithelial cells exposed to UV-B radiation. Exp. Eye Res. 2009, 89, 140–151.
  81. Leerar, J.R.; Glupker, C.D.; Schotanus, M.P.; Ubels, J.L. The effect of K(+) on caspase activity of corneal epithelial cells exposed to UVB. Exp. Eye Res. 2016, 151, 23–25.
  82. Teraki, Y.; Shiohara, T. Apoptosis and the skin. Eur. J. Dermatol. 1999, 9, 413–425, quiz 426.
  83. Cleaver, J.E.; Lam, E.T.; Revet, I. Disorders of nucleotide excision repair: The genetic and molecular basis of heterogeneity. Nat. Rev. Genet. 2009, 10, 756–768.
  84. Masutani, C.; Kusumoto, R.; Yamada, A.; Dohmae, N.; Yokoi, M.; Yuasa, M.; Araki, M.; Iwai, S.; Takio, K.; Hanaoka, F. The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature 1999, 399, 700–704.
  85. Vechtomova, Y.L.; Telegina, T.A.; Kritsky, M.S. Evolution of Proteins of the DNA Photolyase/Cryptochrome Family. Biochemistry 2020, 85, S131–S153.
  86. Roh, D.S.; Du, Y.; Gabriele, M.L.; Robinson, A.R.; Niedernhofer, L.J.; Funderburgh, J.L. Age-related dystrophic changes in corneal endothelium from DNA repair-deficient mice. Aging Cell 2013, 12, 1122–1131.
  87. Storchova, Z.; Pellman, D. From polyploidy to aneuploidy, genome instability and cancer. Nat. Rev. Mol. Cell Biol. 2004, 5, 45–54.
  88. Roh, D.; Du, Y.; Robinson, A.; Gabriele, M.; Niedernhofer, L.; Funderburgh, J. Corneal Endothelial Changes in DNA Repair-Deficient Mice. Investig. Ophthalmol. Vis. Sci. 2010, 51, 4290.
  89. Deshpande, N.; Melangath, G.; Vasanth, S.; Price, M.; Price, F.; Jurkunas, U.V. Defective DNA Repair in Fuchs endothelial corneal dystrophy. Investig. Ophthalmol. Vis. Sci. 2021, 62, 838.
  90. Deshpande, P.; Notara, M.; Bullett, N.; Daniels, J.T.; Haddow, D.B.; MacNeil, S. Development of a Surface-Modified Contact Lens for the Transfer of Cultured Limbal Epithelial Cells to the Cornea for Ocular Surface Diseases. Tissue Eng. Part A 2009, 15, 2889–2902.
  91. Asahina, H.; Han, Z.; Kawanishi, M.; Kato, T., Jr.; Ayaki, H.; Todo, T.; Yagi, T.; Takebe, H.; Ikenaga, M.; Kimura, S.H. Expression of a mammalian DNA photolyase confers light-dependent repair activity and reduces mutations of UV-irradiated shuttle vectors in xeroderma pigmentosum cells. Mutat. Res. 1999, 435, 255–262.
  92. Zwetsloot, J.C.; Vermeulen, W.; Hoeijmakers, J.H.; Yasui, A.; Eker, A.P.; Bootsma, D. Microinjected photoreactivating enzymes from Anacystis and Saccharomyces monomerize dimers in chromatin of human cells. Mutat. Res. 1985, 146, 71–77.
  93. Jans, J.; Schul, W.; Sert, Y.G.; Rijksen, Y.; Rebel, H.; Eker, A.P.; Nakajima, S.; van Steeg, H.; de Gruijl, F.R.; Yasui, A.; et al. Powerful skin cancer protection by a CPD-photolyase transgene. Curr. Biol. 2005, 15, 105–115.
  94. Schul, W.; Jans, J.; Rijksen, Y.M.; Klemann, K.H.; Eker, A.P.; de Wit, J.; Nikaido, O.; Nakajima, S.; Yasui, A.; Hoeijmakers, J.H.; et al. Enhanced repair of cyclobutane pyrimidine dimers and improved UV resistance in photolyase transgenic mice. EMBO J. 2002, 21, 4719–4729.
  95. Zelle, B.; Reynolds, R.J.; Kottenhagen, M.J.; Schuite, A.; Lohman, P.H. The influence of the wavelength of ultraviolet radiation on survival, mutation induction and DNA repair in irradiated Chinese hamster cells. Mutat. Res. 1980, 72, 491–509.
  96. van Zeeland, A.A.; Smith, C.A.; Hanawalt, P.C. Sensitive determination of pyrimidine dimers in DNA of UV-irradiated mammalian cells. Introduction of T4 endonuclease V into frozen and thawed cells. Mutat. Res. 1981, 82, 173–189.
  97. Bohr, V.A.; Smith, C.A.; Okumoto, D.S.; Hanawalt, P.C. DNA repair in an active gene: Removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall. Cell 1985, 40, 359–369.
  98. Collins, A.R.; Mitchell, D.L.; Zunino, A.; de Wit, J.; Busch, D. UV-sensitive rodent mutant cell lines of complementation groups 6 and 8 differ phenotypically from their human counterparts. Environ. Mol. Mutagen. 1997, 29, 152–160.
  99. Boros, G.; Miko, E.; Muramatsu, H.; Weissman, D.; Emri, E.; Rozsa, D.; Nagy, G.; Juhasz, A.; Juhasz, I.; van der Horst, G.; et al. Transfection of pseudouridine-modified mRNA encoding CPD-photolyase leads to repair of DNA damage in human keratinocytes: A new approach with future therapeutic potential. J. Photochem. Photobiol. B 2013, 129, 93–99.
  100. Lopez-Camarillo, C.; Ocampo, E.A.; Casamichana, M.L.; Perez-Plasencia, C.; Alvarez-Sanchez, E.; Marchat, L.A. Protein Kinases and Transcription Factors Activation in Response to UV-Radiation of Skin: Implications for Carcinogenesis. Int. J. Mol. Sci. 2012, 13, 142–172.
  101. Boros, G.; Miko, E.; Muramatsu, H.; Weissman, D.; Emri, E.; van der Horst, G.T.; Szegedi, A.; Horkay, I.; Emri, G.; Kariko, K.; et al. Identification of Cyclobutane Pyrimidine Dimer-Responsive Genes Using UVB-Irradiated Human Keratinocytes Transfected with In Vitro-Synthesized Photolyase mRNA. PLoS ONE 2015, 10, e0131141.
  102. Marizcurrena, J.J.; Martinez-Lopez, W.; Ma, H.; Lamparter, T.; Castro-Sowinski, S. A highly efficient and cost-effective recombinant production of a bacterial photolyase from the Antarctic isolate Hymenobacter sp. UV11. Extremophiles 2019, 23, 49–57.
  103. Yasuda, S.; Sekiguchi, M. T4 endonuclease involved in repair of DNA. Proc. Natl. Acad. Sci. USA 1970, 67, 1839–1845.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Cell Biology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Thomas Volatier
View Times: 792
Revisions: 2 times (View History)
Update Date: 23 Mar 2022
Table of Contents
Video Production Service
Feedback