- Email: [email protected]
Challenging the Central Dogma of Skin Photobiology: Are Proteins More Important than DNA?
E Emanuele Challenging the Central Dogma of Skin Photobiology
David Duggan12, Carolyn Hutter13, Lucia A. Hindorff14, William S. Bush5,15, Charles Kooperberg1, Loic Le Marchand2 and Ulrike Peters1
This work was primarily performed in Seattle, Washington, USA; additional work performed in Boston, Massachusetts, USA; Honolulu, Hawaii, USA; Nashville, Tennessee, USA.
1
Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; 2Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA; 3Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 4Department of Epidemiology, Fairbanks School of Public Health, Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA; 5Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA; 6 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA; 7Cancer Prevention Institute of California, Fremont, California, USA; 8 Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; 9Information Sciences Institute, University of Southern California, Marina del Rey, California, USA; 10 Department of Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; 11Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts, USA; 12Translational Genomics Research Institute, Phoenix, Arizona, USA; 13 Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, NCI, NIH, Bethesda, Maryland, USA; 14Division of Genomic Medicine, NHGRI, NIH, Bethesda, Maryland, USA and 15Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA E-mail: [email protected] or [email protected]
SUPPLEMENTARY MATERIAL
REFERENCES Bishop DT, Demenais F, Iles MM et al. (2009) Genome-wide association study identifies three loci associated with melanoma risk. Nat Genet 41:920–5 Brown KM, Macgregor S, Montgomery GW et al. (2008) Common sequence variants on 20q11.22 confer melanoma susceptibility. Nat Genet 40:838–40 Cook AL, Chen W, Thurber AE et al. (2009) Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci. J Invest Dermatol 129:392–405 Duffy DL, Zhao ZZ, Sturm RA et al. (2010) Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma. J Invest Dermatol 130:520–8 Falchi M, Bataille V, Hayward NK et al. (2009) Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat Genet 41:915–9 Fernandez LP, Milne RL, Pita G et al. (2008) SLC45A2: a novel malignant melanoma-associated gene. Hum Mutat 29:1161–7 Gerstenblith MR, Shi J, Landi MT (2010) Genomewide association studies of pigmentation and skin cancer: a review and meta-analysis. Pigment Cell Melanoma Res 23:587–606 Gruber SB, Armstrong BK (2006) Cutaneous and ocular melanoma. In: Schottenfeld D, Fraumeni JF (eds) Cancer Epidemiology and Prevention, 3rd edn. Oxford University Press: USA: New York, NY, 1126–229
Guedj M, Bourillon A, Combadieres C et al. (2008) Variants of the MATP/SLC45A2 gene are protective for melanoma in the French population. Hum Mutat 29:1154–60 Howlader NNA, Krapcho M, Garshell J et al. (eds) (2013) SEER Cancer Statistics Review, 19752010 ohttp://seer.cancer.gov/csr/1975_2010/4, Accessed based on November 2012 SEER data submission, posted to the SEER website Joosse A, de Vries E, Eckel R et al. (2011) Gender differences in melanoma survival: female patients have a decreased risk of metastasis. J Invest Dermatol 131:719–26 Kim NH, Cheong KA, Lee TR et al. (2012) PDZK1 upregulation in estrogen-related hyperpigmentation in melasma. J Invest Dermatol 132:2622–31 Kondo T, Hearing VJ (2011) Update on the regulation of mammalian melanocyte function and skin pigmentation. Expert Rev Dermatol 6:97–108 Matise TC, Ambite JL, Buyske S et al. (2011) The Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study. Am J Epidemiol 174:849–59 Randall JC, Winkler TW, Kutalik Z et al. (2013) Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. PLoS Genet 9:e1003500 Scherer D, Kumar R (2010) Genetics of pigmentation in skin cancer—a review. Mutat Res 705:141–53 Stokowski RP, Pant PV, Dadd T et al. (2007) A genomewide association study of skin pigmentation in a South Asian population. Am J Hum Genet 81:1119–32 Tadokoro T, Rouzaud F, Itami S et al. (2003) The inhibitory effect of androgen and sexhormone-binding globulin on the intracellular cAMP level and tyrosinase activity of normal human melanocytes. Pigment Cell Res 16:190–7
Challenging the Central Dogma of Skin Photobiology: Are Proteins More Important than DNA? Journal of Investigative Dermatology (2014) 134, 2052–2053; doi:10.1038/jid.2014.64; published online 6 March 2014
TO THE EDITOR I read with interest the paper by Gueranger et al. (2013) who showed that a fully functional DNA repair proteome is a crucial prerequisite for the removal of harmful DNA lesions after exposure of the skin to UVR. The authors elegantly show that oxidative protein damage
induced by UVR precedes DNA damage, ultimately resulting in compromised DNA break-rejoining, base, and nucleotide excision repair. Because DNA repair pathways consist of repair proteins (Lagerwerf et al., 2011), it is not surprising that lossof-function of key DNA repair proteins may have serious consequences in terms
Accepted article preview online 3 February 2014; published online 6 March 2014
2052 Journal of Investigative Dermatology (2014), Volume 134
of genome stability. The paper by Gueranger et al. (2013) is extremely interesting because it challenges the current central dogma of photobiology, stating that molecular alterations to DNA have the central role in UVR-induced cell damage and skin carcinogenesis (Nakanishi et al., 2009; Elmets and Athar, 2013). In accordance with the hypothesis that proteins—and not DNA—are the main
Q Gueranger et al. Response to Emanuele
biological targets of UVR in living cells, fresh insights into the role of protein oxidation in photobiology have recently come from extremophile bacteria such as Deinococcus radiodurans, which is characterized by an impressive ability to resist extremely high doses of UVR (500 J m 2) (Daly, 2012). Puzzlingly enough, the extreme resistance of D. radiodurans to UVR is not chiefly dependent on an efficient DNA repair system (Daly, 2012). By contrast, protection against protein oxidative damage is the main mechanism of D. radiodurans adaptation to UVR exposure (Slade and Radman, 2011). Strikingly, other UVR-resistant species like bdelloid rotifers have substantially lower protein oxidation levels than do sensitive organisms, despite a similar yield of DNA double-strand breaks following UVR exposure (Krisko et al., 2012). Therefore, the resistance to UVR critically depends on an efficient proteome protection (but not DNA protection) against UVR-induced oxidation (Krisko and Radman, 2010; Slade and Radman, 2011). In general, extremophiles are able to achieve an exceptional resistance to UVR via simple nonenzymatic antioxidant mechanisms consisting of manganese ions complexed either with low-molecular-weight peptides (Daly, 2012) or trehalose (Webb and DiRuggiero, 2012), which can protect the cell proteome from oxidation and carbonylation due to their high scavenging capacity (Slade and Radman, 2011). Due to recent discoveries in the field of UVR-resistant organisms, it is likely that the next years will see a Copernican Revolution in the field of photoprotection as the research interest will shift from a DNA-centered view of UVR-induced damage to a protein-centered model
where a reduced resistance to UVR is caused primarily by oxidative damage to proteins, with consequential loss of maintenance activities including DNA repair (Slade and Radman, 2011). This view is not at all in antithesis with the proven usefulness of DNA repair enzymes in photoprotection (Berardesca et al., 2012; Emanuele et al., 2013): enzymes are indeed proteins, and thus supply the function of endogenous repair proteins oxidized by prolonged UVR exposure. Such findings have important implications for skin carcinogenesis. Muller and Woods (2013) have recently shown that exposure to UVR elicits an activation of DNA repair proteins aimed at counteracting the well-known detrimental effects of UVR on the cell’s genome. Similarly, Perluigi et al. (2010) have reported that a relevant oxidation of specific proteins occurs in UVB-irradiated human epithelial keratinocytes. These dysfunctional oxidized proteins might result in cell homeostasis impairment and therefore eventually promote carcinogenesis. Besides traditional sunscreens, it is likely that the future in photoprotection and prevention of skin cancer will see at least two exciting milestones, that is, (1) the topical application of xenogenic DNA repair enzymes (that may overcome the reduced repaired capacity of dysfunctional exogenous DNA repair enzymes following oxidation due to repeated UVR exposures); and (2) the protection of the skin proteome against oxidation, which would in turn preserve the genomic integrity of keratinocytes. CONFLICT OF INTEREST The author states no conflict of interest.
Enzo Emanuele1 1
Living Research s.a.s., Robbio (PV), Italy E-mail: [email protected]
REFERENCES Berardesca E, Bertona M, Altabas K et al. (2012) Reduced ultraviolet-induced DNA damage and apoptosis in human skin with topical application of a photolyase-containing DNA repair enzyme cream: clues to skin cancer prevention. Mol Med Rep 5:570–4 Daly MJ (2012) Death by protein damage in irradiated cells. DNA Repair (Amst) 11:12–21 Elmets CA, Athar M (2013) Milestones in photocarcinogenesis. J Invest Dermatol 133:E13–7 Emanuele E, Altabas V, Altabas K et al. (2013) Topical application of preparations containing DNA repair enzymes prevents ultravioletinduced telomere shortening and c-FOS proto-oncogene hyperexpression in human skin: an experimental pilot study. J Drugs Dermatol 12:1017–21 Gueranger Q, Li F, Peacock M et al. (2013) Protein oxidation and DNA repair inhibition by 6-thioguanine and UVA radiation. J Invest Dermatol 134:1408–17 Krisko A, Leroy M, Radman M et al. (2012) Extreme anti-oxidant protection against ionizing radiation in bdelloid rotifers. Proc Natl Acad Sci USA 109:2354–7 Krisko A, Radman M (2010) Protein damage and death by radiation in Escherichia coli and Deinococcus radiodurans. Proc Natl Acad Sci USA 107:14373–7 Lagerwerf S, Vrouwe MG, Overmeer RM et al. (2011) DNA damage response and transcription. DNA Repair (Amst) 10:743–50 Muller HK, Woods GM (2013) Ultraviolet radiation effects on the proteome of skin cells. Adv Exp Med Biol 990:111–9 Nakanishi M, Niida H, Murakami H et al. (2009) DNA damage responses in skin biology— implications in tumor prevention and aging acceleration. J Dermatol Sci 56:76–81 Perluigi M, Di Domenico F, Blarzino C et al. (2010) Effects of UVB-induced oxidative stress on protein expression and specific protein oxidation in normal human epithelial keratinocytes: a proteomic approach. Proteome Sci 8:13 Slade D, Radman M (2011) Oxidative stress resistance in Deinococcus radiodurans. Microbiol Mol Biol Rev 75:133–91 Webb KM, DiRuggiero D (2012) Role of Mn2 þ and compatible solutes in the radiation resistance of thermophilic bacteria and archaea. Archaea 2012:845756
Response to Emanuele Journal of Investigative Dermatology (2014) 134, 2053–2055; doi:10.1038/jid.2014.67; published online 27 February 2014
TO THE EDITOR We thank Dr Emanuele (2014) for his perceptive comments on our recent
paper (Gueranger et al., 2013). We should point out, however, that it is not our intention to displace DNA
Accepted article preview online 3 February 2014; published online 27 February 2014
from its starring role in the central dogma of skin photobiology but rather to suggest that DNA repair proteins share the limelight. UVB-induced DNA damage, cyclobutane pyrimidine dimers www.jidonline.org 2053
David Duggan12, Carolyn Hutter13, Lucia A. Hindorff14, William S. Bush5,15, Charles Kooperberg1, Loic Le Marchand2 and Ulrike Peters1
This work was primarily performed in Seattle, Washington, USA; additional work performed in Boston, Massachusetts, USA; Honolulu, Hawaii, USA; Nashville, Tennessee, USA.
1
Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; 2Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA; 3Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 4Department of Epidemiology, Fairbanks School of Public Health, Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA; 5Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA; 6 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA; 7Cancer Prevention Institute of California, Fremont, California, USA; 8 Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; 9Information Sciences Institute, University of Southern California, Marina del Rey, California, USA; 10 Department of Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; 11Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts, USA; 12Translational Genomics Research Institute, Phoenix, Arizona, USA; 13 Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, NCI, NIH, Bethesda, Maryland, USA; 14Division of Genomic Medicine, NHGRI, NIH, Bethesda, Maryland, USA and 15Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA E-mail: [email protected] or [email protected]
SUPPLEMENTARY MATERIAL
REFERENCES Bishop DT, Demenais F, Iles MM et al. (2009) Genome-wide association study identifies three loci associated with melanoma risk. Nat Genet 41:920–5 Brown KM, Macgregor S, Montgomery GW et al. (2008) Common sequence variants on 20q11.22 confer melanoma susceptibility. Nat Genet 40:838–40 Cook AL, Chen W, Thurber AE et al. (2009) Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci. J Invest Dermatol 129:392–405 Duffy DL, Zhao ZZ, Sturm RA et al. (2010) Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma. J Invest Dermatol 130:520–8 Falchi M, Bataille V, Hayward NK et al. (2009) Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat Genet 41:915–9 Fernandez LP, Milne RL, Pita G et al. (2008) SLC45A2: a novel malignant melanoma-associated gene. Hum Mutat 29:1161–7 Gerstenblith MR, Shi J, Landi MT (2010) Genomewide association studies of pigmentation and skin cancer: a review and meta-analysis. Pigment Cell Melanoma Res 23:587–606 Gruber SB, Armstrong BK (2006) Cutaneous and ocular melanoma. In: Schottenfeld D, Fraumeni JF (eds) Cancer Epidemiology and Prevention, 3rd edn. Oxford University Press: USA: New York, NY, 1126–229
Guedj M, Bourillon A, Combadieres C et al. (2008) Variants of the MATP/SLC45A2 gene are protective for melanoma in the French population. Hum Mutat 29:1154–60 Howlader NNA, Krapcho M, Garshell J et al. (eds) (2013) SEER Cancer Statistics Review, 19752010 ohttp://seer.cancer.gov/csr/1975_2010/4, Accessed based on November 2012 SEER data submission, posted to the SEER website Joosse A, de Vries E, Eckel R et al. (2011) Gender differences in melanoma survival: female patients have a decreased risk of metastasis. J Invest Dermatol 131:719–26 Kim NH, Cheong KA, Lee TR et al. (2012) PDZK1 upregulation in estrogen-related hyperpigmentation in melasma. J Invest Dermatol 132:2622–31 Kondo T, Hearing VJ (2011) Update on the regulation of mammalian melanocyte function and skin pigmentation. Expert Rev Dermatol 6:97–108 Matise TC, Ambite JL, Buyske S et al. (2011) The Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study. Am J Epidemiol 174:849–59 Randall JC, Winkler TW, Kutalik Z et al. (2013) Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. PLoS Genet 9:e1003500 Scherer D, Kumar R (2010) Genetics of pigmentation in skin cancer—a review. Mutat Res 705:141–53 Stokowski RP, Pant PV, Dadd T et al. (2007) A genomewide association study of skin pigmentation in a South Asian population. Am J Hum Genet 81:1119–32 Tadokoro T, Rouzaud F, Itami S et al. (2003) The inhibitory effect of androgen and sexhormone-binding globulin on the intracellular cAMP level and tyrosinase activity of normal human melanocytes. Pigment Cell Res 16:190–7
Challenging the Central Dogma of Skin Photobiology: Are Proteins More Important than DNA? Journal of Investigative Dermatology (2014) 134, 2052–2053; doi:10.1038/jid.2014.64; published online 6 March 2014
TO THE EDITOR I read with interest the paper by Gueranger et al. (2013) who showed that a fully functional DNA repair proteome is a crucial prerequisite for the removal of harmful DNA lesions after exposure of the skin to UVR. The authors elegantly show that oxidative protein damage
induced by UVR precedes DNA damage, ultimately resulting in compromised DNA break-rejoining, base, and nucleotide excision repair. Because DNA repair pathways consist of repair proteins (Lagerwerf et al., 2011), it is not surprising that lossof-function of key DNA repair proteins may have serious consequences in terms
Accepted article preview online 3 February 2014; published online 6 March 2014
2052 Journal of Investigative Dermatology (2014), Volume 134
of genome stability. The paper by Gueranger et al. (2013) is extremely interesting because it challenges the current central dogma of photobiology, stating that molecular alterations to DNA have the central role in UVR-induced cell damage and skin carcinogenesis (Nakanishi et al., 2009; Elmets and Athar, 2013). In accordance with the hypothesis that proteins—and not DNA—are the main
Q Gueranger et al. Response to Emanuele
biological targets of UVR in living cells, fresh insights into the role of protein oxidation in photobiology have recently come from extremophile bacteria such as Deinococcus radiodurans, which is characterized by an impressive ability to resist extremely high doses of UVR (500 J m 2) (Daly, 2012). Puzzlingly enough, the extreme resistance of D. radiodurans to UVR is not chiefly dependent on an efficient DNA repair system (Daly, 2012). By contrast, protection against protein oxidative damage is the main mechanism of D. radiodurans adaptation to UVR exposure (Slade and Radman, 2011). Strikingly, other UVR-resistant species like bdelloid rotifers have substantially lower protein oxidation levels than do sensitive organisms, despite a similar yield of DNA double-strand breaks following UVR exposure (Krisko et al., 2012). Therefore, the resistance to UVR critically depends on an efficient proteome protection (but not DNA protection) against UVR-induced oxidation (Krisko and Radman, 2010; Slade and Radman, 2011). In general, extremophiles are able to achieve an exceptional resistance to UVR via simple nonenzymatic antioxidant mechanisms consisting of manganese ions complexed either with low-molecular-weight peptides (Daly, 2012) or trehalose (Webb and DiRuggiero, 2012), which can protect the cell proteome from oxidation and carbonylation due to their high scavenging capacity (Slade and Radman, 2011). Due to recent discoveries in the field of UVR-resistant organisms, it is likely that the next years will see a Copernican Revolution in the field of photoprotection as the research interest will shift from a DNA-centered view of UVR-induced damage to a protein-centered model
where a reduced resistance to UVR is caused primarily by oxidative damage to proteins, with consequential loss of maintenance activities including DNA repair (Slade and Radman, 2011). This view is not at all in antithesis with the proven usefulness of DNA repair enzymes in photoprotection (Berardesca et al., 2012; Emanuele et al., 2013): enzymes are indeed proteins, and thus supply the function of endogenous repair proteins oxidized by prolonged UVR exposure. Such findings have important implications for skin carcinogenesis. Muller and Woods (2013) have recently shown that exposure to UVR elicits an activation of DNA repair proteins aimed at counteracting the well-known detrimental effects of UVR on the cell’s genome. Similarly, Perluigi et al. (2010) have reported that a relevant oxidation of specific proteins occurs in UVB-irradiated human epithelial keratinocytes. These dysfunctional oxidized proteins might result in cell homeostasis impairment and therefore eventually promote carcinogenesis. Besides traditional sunscreens, it is likely that the future in photoprotection and prevention of skin cancer will see at least two exciting milestones, that is, (1) the topical application of xenogenic DNA repair enzymes (that may overcome the reduced repaired capacity of dysfunctional exogenous DNA repair enzymes following oxidation due to repeated UVR exposures); and (2) the protection of the skin proteome against oxidation, which would in turn preserve the genomic integrity of keratinocytes. CONFLICT OF INTEREST The author states no conflict of interest.
Enzo Emanuele1 1
Living Research s.a.s., Robbio (PV), Italy E-mail: [email protected]
REFERENCES Berardesca E, Bertona M, Altabas K et al. (2012) Reduced ultraviolet-induced DNA damage and apoptosis in human skin with topical application of a photolyase-containing DNA repair enzyme cream: clues to skin cancer prevention. Mol Med Rep 5:570–4 Daly MJ (2012) Death by protein damage in irradiated cells. DNA Repair (Amst) 11:12–21 Elmets CA, Athar M (2013) Milestones in photocarcinogenesis. J Invest Dermatol 133:E13–7 Emanuele E, Altabas V, Altabas K et al. (2013) Topical application of preparations containing DNA repair enzymes prevents ultravioletinduced telomere shortening and c-FOS proto-oncogene hyperexpression in human skin: an experimental pilot study. J Drugs Dermatol 12:1017–21 Gueranger Q, Li F, Peacock M et al. (2013) Protein oxidation and DNA repair inhibition by 6-thioguanine and UVA radiation. J Invest Dermatol 134:1408–17 Krisko A, Leroy M, Radman M et al. (2012) Extreme anti-oxidant protection against ionizing radiation in bdelloid rotifers. Proc Natl Acad Sci USA 109:2354–7 Krisko A, Radman M (2010) Protein damage and death by radiation in Escherichia coli and Deinococcus radiodurans. Proc Natl Acad Sci USA 107:14373–7 Lagerwerf S, Vrouwe MG, Overmeer RM et al. (2011) DNA damage response and transcription. DNA Repair (Amst) 10:743–50 Muller HK, Woods GM (2013) Ultraviolet radiation effects on the proteome of skin cells. Adv Exp Med Biol 990:111–9 Nakanishi M, Niida H, Murakami H et al. (2009) DNA damage responses in skin biology— implications in tumor prevention and aging acceleration. J Dermatol Sci 56:76–81 Perluigi M, Di Domenico F, Blarzino C et al. (2010) Effects of UVB-induced oxidative stress on protein expression and specific protein oxidation in normal human epithelial keratinocytes: a proteomic approach. Proteome Sci 8:13 Slade D, Radman M (2011) Oxidative stress resistance in Deinococcus radiodurans. Microbiol Mol Biol Rev 75:133–91 Webb KM, DiRuggiero D (2012) Role of Mn2 þ and compatible solutes in the radiation resistance of thermophilic bacteria and archaea. Archaea 2012:845756
Response to Emanuele Journal of Investigative Dermatology (2014) 134, 2053–2055; doi:10.1038/jid.2014.67; published online 27 February 2014
TO THE EDITOR We thank Dr Emanuele (2014) for his perceptive comments on our recent
paper (Gueranger et al., 2013). We should point out, however, that it is not our intention to displace DNA
Accepted article preview online 3 February 2014; published online 27 February 2014
from its starring role in the central dogma of skin photobiology but rather to suggest that DNA repair proteins share the limelight. UVB-induced DNA damage, cyclobutane pyrimidine dimers www.jidonline.org 2053