Ultraviolet (UV) radiation is one of the most common environmental health hazards that cause highly toxic effects in most living organisms. UV irradiation leads to harmful effects including skin aging, eye damage, and skin cancer because of increased production of cellular reactive oxygen species and by direct DNA damage. Damaged DNA, if not properly repaired, is a source of mutation, and interferes with many cellular mechanisms such as replication, transcription, and the cell cycle. Because most UV damaged DNA is efficiently repaired by nucleotide excision repair (NER), which is a specialized UV-induced DNA damage repair system, many UV-induced symptoms are closely related to NER. Therefore, understanding the function of NER genes will elucidate the cause of different UV-induced symptoms. Furthermore, a multidisciplinary understanding of damaged DNA repair systems and other cellular mechanisms affected by unrepaired DNA damage would lead to an improved understanding of UV-induced symptoms and toward developing various preventive and therapeutic methods against UV damage. For this purpose, in this review we discuss two NER-related human genetic disorders, xeroderma pigmentosum (XP) and Cockayne syndrome (CS), the cellular mechanisms that are impaired by defective NER genes, and the functions of RAD2/XPG in relation to the cause of various UV damage-induced symptoms.
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Yagura, T., Makita, K., Yamamoto, H., Menck, C. F. M. & Schuch, A. P. Biological sensors for solar ultraviolet radiation. Sensors 11:4277–4294 (2011).
Amaro-Ortiz, A., Yan, B. & D’Orazio, J. A. Ultraviolet radiation, aging and the skin: Prevention of damage by topical cAMP manipulation. Molecules 19:6202–6219 (2014).
Holick, M. F. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 80(suppl): 1678S–1688S (2004).
Hoeijmakers, J. H. J. Genome maintenance mechanisms for preventing cancer. Nature 411:366–374 (2001).
Lee, S.-K., Yu, S.-L., Prakash, L. & Prakash, S. Requirement of yeast RAD2, a homolog of human XPG gene, for efficient RNA polymerase II transcription: implication for Cockayne syndrome. Cell 109:823–834 (2002).
Kang, M.-S. et al. Mitotic catastrophe induced by overexpression of budding yeast Rad2p. Yeast 27:399–411 (2010).
Kang, M.-S. et al. Yeast RAD2, a homolog of human XPG, plays a key role in the regulation of the cell cycle and actin dynamics. Biol Open 3:29–41 (2014).
Norval, M. et al. The human health effects of ozone depletion and interactions with climate change. Photochem Photobiol Sci 10:199–225 (2011).
Egly, J.-M. & Coin, F. A history of TFIIH: Two decades of molecular biology on a pivotal transcription/repair factor. DNA Repair 10:714–721 (2011).
Nouspikel, T. Nucleotide excision repair: variations on versatility. Cell Mol Life Sci 66:994–1009 (2009).
Edifizi, D. & Schumacher, B. Genome instability in development and aging: Insights from nucleotide excision repair in humans, mice, and worms. Biomolecules 5:1855–1869 (2015).
DiGiovanna, J. J. & Kraemer, K. H. Shining a light on xeroderma pigmentosum. J Invest Dermatol 132:785–796 (2012).
Kraemer, K. H., Lee, M.-M., Andrews, A. D. & Lambert, W. C. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. Arch Dermatol 130:1018–1021 (1994).
Lehmann, A. R., McGibbon, D. & Stefanini, M. Xeroderma pigmentosum. Orphanet J Rare Dis 6:70 (2011).
Laugel, V. Cockayne syndrome: The expanding clinical and mutational spectrum. Mech Ageing Develop 134:167–170 (2013).
Lindenbaum, Y. et al. Xeroderma pigmentosum/Cockayne syndrome complex: first neuropathological study and review of eight other cases. Eur J paed Neur 5:225–242 (2001).
Nance, M. A. & Berry, S. A. Cockayne syndrome: review of 140 cases. Am J Med Genet 42:68–84 (1992).
Kubota, M. et al. Nationwide survey of Cockayne syndrome in Japan: Incidence, clinical course and prognosis. Ped Int 57:339–347 (2015).
Zhang, W. R., Garrett, G. L., Cleaver, J. E. & Arron, S. T. Absence of skin cancer in the DNA repair-deficient disease Cockayne syndrome (CS): A survey study. J Am Acad Dermatol 74:1270–1272 (2016).
Vidak, S. & Foisner, R. Molecular insights into the premature aging disease progeria. Histochem Cell Biol 145:401–417 (2016).
Navarro, C. L., Cau, P. & Lévy, N. Molecular bases of progeriod syndromes. Human Mol Genet 15:R151–R161 (2006).
Proietti-De-Santis, L., Drané, P. & Egly, J.-M. Cockayne syndrome B protein regulates the transcription program after UV irradiation. EMBO J 25:1915–1923 (2006).
Fousteri, M., Vermeulen, W., van Zeeland, A. A. & Mullenders, L. H. F. Cockayne syndrome A and B protein differentially regulate recruitment of chromatin remodeling and repair factors to stalled RNA polymerase II in vivo. Mol Cell 23:471–482 (2006).
Schärer, O. D. The molecular basis for different disease states caused by mutations in TFIIH and XPG. DNA repair 7:339–344 (2008).
Narita, T., Narita, K., Takedachi, A., Saijo, M. & Tanaka, K. Regulation of transcription elongation by the XPG-TFIIH complex is implicated in Cockayne syndrome. Mol Cell Biol 35:3178–3188 (2015).
Reid-Bayliss, K. S., Arron, S. T., Loeb, L. A., Bezrookove, V. & Cleaver, J. E. Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency. Proc Natl Acad Sci USA 113:10151–10156 (2016).
Kaeberlein, M. Lessons on longevity from budding yeast. Nature 464:513–519 (2010).
Lee, S.-K., Johnson, R. E., Yu, S.-L., Prakash, L. & Prakash, S. Requirement of yeast SGS1 and SRS2 genes for replication and transcription. Science 286:2339–2342 (1999).
Constantinou, A. et al. Conserved residues of human XPG protein important for nuclease activity and function in nucleotide excision repair. J Biol Chem 274:5637–5648 (1999).
Clarkson, S. G. The XPG story. Biochimie 85:1113–1121 (2003).
Gary, R., Ludwig, D. L., Cornelius, H. L., MacInnes, M. A. & Park, M. S. The DNA repair endonuclease XPG binds to proliferating cell nuclear antigen (PCNA) and shares sequence elements with the PCNA-binding regions of FEN-1 and cyclin-dependent kinase inhibitor p21. J Biol Chem 272:24522–24529 (1997).
Shiomi, N. et al. Identification of the XPG region that causes the onset of Cockayne syndrome by using Xpg mutant mice generated by the cDNA-mediated knockin method. Mol Cell Biol 24:3712–3719 (2004).
Yu, S.-L. et al. The PCNA binding domain of Rad2p plays a role in mutagenesis by modulating the cell cycle in response to DNA damage. DNA Repair 16:1–10 (2014).
Trego, K. S. et al. The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome. Cell Cycle 10:1998–2007 (2011).
Ito, S. et al. XPG stabilizes TFIIH, allowing transactivation of nuclear receptors: Implications for Cockayne syndrome in XP-G/CS patients. Mol Cell 26:231–243 (2007).
Iyer, N., Reagan, M. S., Wu, K.-J., Canagarajah, B. & Friedberg, E. C. Interactions involving the human RNA polymerase II transcription/nucleotide excision repair complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein. Biochemistry 35:2157–2167 (1996).
Nouspikel, T., Lalle, P., Leadon, S. A., Cooper, P. K. & Clarkson, S. G. A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G: Implications for a second XPG function. Proc Natl Acad Sci USA 94:3116–3121 (1997).
Nicolet, C. M. & Friedberg, E. C. Overexpression of the RAD2 gene of Saccharomyces cerevisiae: Identification and preliminary characterization of Rad2 protein. Yeast 3:149–160 (1987).
Weinert, T. DNA damage checkpoints update: getting molecular. Curr Opin Genet Develop 8:185–193 (1998).
Batenburg, N., Thompson, E. L., Hendrickson, E. A. & Zhu, X.-D. Cockayne syndrome group B protein regulates DNA double-strand break repair and checkpoint activation. EMBO J 34:1399–1416 (2015).
Formigli, L., Meacci, E., Zecchi-Orlandini, S. & Orlandini, G. E. Cytoskeletal reorganization in skeletal muscle differentiation: from cell morphology to gene expression. Eur J Histochem 51(supp 1):21–28 (2007).
Pollard, T. D. & Cooper, J. A. Actin, a central player in cell shape and movement. Science 326:1208–1212 (2009).
Hsu, F.-F., Lin, T.-Y., Chen, J.-Y. & Shieh, S.-Y. P53-mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control. Oncogene 29:2864–2876 (2010).
Pruyne, D. & Bretscher, A. Polarization of cell growth in yeast. I. Establishment and maintenance of polarity states. J Cell Sci 113:365–375 (2000).
Goellner, B. & Aberle, H. The synaptic cytoskeleton in development and disease. Develop Neurobiol 72:111–125 (2012).
Revert, I., Feeney, L., Tang, A. A., Huang, E. J. & Cleaver, J. E. Dysmyelination not demyelination causes neurological symptoms in preweaned mice in a murine model of Cockayne syndrome. Proc Natl Acad Sci USA 109:4627–4632 (2012).
McMurray, C. T. Neurodegeneration: diseases of the cytoskeleton? Cell Death Differen 7:861–865 (2000).
Hotulainen, P. & Hoogenraad, C. C. Actin in dendritic spines: connecting dynamics to function. J Cell Biol 189:619–629 (2010).
Tomicic, M. T. et al. Delayed c-Fos activation in human cells triggers XPF induction and an adaptive response to UVC-induced DNA damage and cytotoxicity. Cell Mol Life Sci 38:1785–1798 (2011).
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Yu, SL., Lee, SK. Ultraviolet radiation: DNA damage, repair, and human disorders. Mol. Cell. Toxicol. 13, 21–28 (2017). https://doi.org/10.1007/s13273-017-0002-0
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