Die Entdeckung, daß sichtbares Licht notwendig ist, um die Schädigung durch UV-Strahlung zumindest teilweise zu kompensieren [Kelner, 1949Kelner, Albert (1949): Effect of visible light on the recovery of \emphStreptomyces griseus conidia from ultra-violet irradiation injury., Proceedings of the National Academy of Sciences, USA 35:73-79], liegt nun genau sechzig Jahre zurück. Nur etwa zehn Jahre nach dieser Entdeckung wurde ein Enzym, das UV-Schäden in der DNA repariert, aus Bäckerhefe extrahiert [Rupert, 1960Rupert, Claud S. (1960): Photoreactivation of Transforming DNA by an Enzyme from Bakers' Yeast, Journal of General Physiology 43:573-595] und biochemisch charakterisiert [Rupert, 1962Rupert, Claud S. (1962): Photoenzymatic Repair of Ultraviolet Damage in DNA I. Kinetics of the reaction, Journal of General Physiology 45:703-724, Rupert, 1962Rupert, Claud S. (1962): Photoenzymatic Repair of Ultraviolet Damage in DNA II. Formation of an enzyme-substrate complex, Journal of General Physiology 45:725-741]. Schnell wurde deutlich, daß Photolyasen, wie die Proteine bald genannt wurden, in einer taxonomisch sehr breiten Gruppe von Organismen durch alle Reiche der Lebewesen vorkommen. Biochemische und spektroskopische Untersuchungen ergaben, daß es sich bei Photolyasen um Flavoproteine handelt [Iwatsuki, 1980Iwatsuki, Norio; Joe, Cheol O.; Werbin, Harold (1980): Evidence That Deoxyribonucleic Acid Photolyase from Baker's Yeast Is a Flavoprotein, Biochemistry 19:1172-1176, Sancar, 1984Sancar, Aziz; Sancar, Gwendolyn B. (1984): \emphEscherichia coli DNA Photolyase is a Flavoprotein, Journal of Molecular Biology 172:223-227]. Der zweite enthaltene Kofaktor konnte als 5,10-Methenyltetrahydrofolat (MTHF) in DNA-Photolyase aus Escherichia coli [Johnson, 1988Johnson, Jean L.; Hamm-Alvarez, Sarah; Payne, Gillian; Sancar, Gwendolyn B.; Rajagopalan, K.V.; Sancar, Aziz (1988): Identification of the second chromophore of \emphEscherichia coli and yeast DNA photolyases as 5,10-methenyltetrahydrofolate, Proceedings of the National Academy of Sciences, USA 85:2046-2050], als 8-Hydroxy-5-deazaflavin (8-HDF) in DNA-Photolyase aus Anacystis nidulans [Eker, 1990Eker, Andries P. M.; Kooiman, Patricia; Hessels, Johanna K. C.; Yasui, Akira (1990): DNA photoreactivating enzyme from the cyanobacterium \emphAnacystis nidulans, Journal of Biological Chemistry 265:8009-8015, Tamada, 1997Tamada, Taro; Kitadokoro, Kengo; Higuchi, Yoshiki; Inaka, Koji; Yasui, Akira; de Ruiter, Petra E.; Eker, Andre P. M.; Miki, Kunio (1997): Crystal structure of DNA photolyase from \emphAnacystis nidulans, Nature Structural Biology 4:887-891] und als Flavinmononukleotid (FMN) in DNA-Photolyase aus Thermus thermophilus [Klar, 2006Klar, Tobias; Kaiser, Gebhard; Hennecke, Ulrich; Carell, Thomas; Batschauer, Alfred; Essen, Lars-Oliver (2006): Natural and Non-natural Antenna Chromophores in the DNA Photolyase from \emphThermus Thermophilus, ChemBioChem 7:1798-1806] charakterisiert werden. Ein Meilenstein war die Veröffentlichung der Kristallstruktur der DNA-Photolyase aus E. coli [Park, 1995Park, Hee-Won; Kim, Sang-Tae; Sancar, Aziz; Deisenhofer, Johann (1995): Crystal Structure of DNA Photolyase from \emphEscherichia coli, Science 268:1866-1872]. Seither wird dieses Enzym als Modell für die gesamte Proteinfamilie benutzt. Eine bedeutsame Erkenntnis aus der Kristallstruktur war die ungewöhnliche¹⁾, U-förmige Anordnung des FAD-Kofaktors, bei der der Adeninring in van-der-Waals-Kontakt über dem Isoalloxazinring zu liegen kommt. Diese Anordnung konnte seitdem für alle weiteren Kristallstrukturen von Mitgliedern der Proteinfamilie bestätigt werden.

Cryptochrome wurden im Gegensatz zu den Photolyasen erst vor relativ kurzer Zeit als Proteine entdeckt (HY4-Mutante von Arabidopsis thaliana) und zunächst biochemisch charakterisiert [Ahmad, 1993Ahmad, Margaret; Cashmore, Anthony R. (1993): \emphHY4 gene of \emphA. thaliana encodes a protein with characteristics of a blue-light photoreceptor, Nature 366:162-166]. Es stellte sich dabei heraus, daß sie den Photolyasen in Sequenz und Struktur sehr ähnlich sind, was später durch die Kristallstruktur von Cryptochrom-1 aus A. thaliana [Brautigam, 2004Brautigam, Chad A.; Smith, Barbara S.; Ma, Zhiquan; Palnitkar, Maya; Tomchick, Diana R.; Machius, Mischa; Deisenhofer, Johann (2004): Structure of the photolyase-like domain of cryptochrome 1 from \emphArabidopsis thaliana, Proceedings of the National Academy of Sciences, USA 101:12142-12147] bestätigt wurde.

Abb. 1: Vereinfachter molekularer Stammbaum (unrooted phylogenetic tree) der Photolyase–Cryptochrom–Proteinfamilie, der die unterschiedlichen Cluster innerhalb der Familie und die Ähnlichkeit der Cluster untereinander hervorhebt. Nach [Brudler, 2003Brudler, Ronald; Hitomi, Kenichi; Daiyasu, Hiromi; Toh, Hiroyuki; Kucho, Ken-ichi; Ishiura, Massahiro; Kaneshisa, Minoru; Roberts, Victoria A.; Todo, Takeshi; Tainer, John A.; Getzoff, Elisabeth D. (2003): Identification of a New Cryptochrome Class: Structure, Function, and Evolution, Molecular Cell 11:59-67], verändert.

Durch die zunehmende Verfügbarkeit von Gensequenzen und deren Durchsuchbarkeit in Datenbanken wurden kurz nach der Entdeckung der Cryptochrome in Pflanzen auch in Tieren den Photolyasen homologe Gene gefunden und charakterisiert [Spek, 1996van der Spek, P. J.; Kobayashi, K.; Bootsma, D.; Takao, M.; Eker, André P. M.; Yasui, A. (1996): Cloning, Tissue Expression, and Mapping of a Human Photolyase Homolog with Similarity to Plant Blue-Light Receptors, Genomics 37:177-182, Todo, 1996Todo, Takeshi; Ryo, Haruko; Yamamoto, Kazuo; Toh, Hiroyuki; Inui, Taiichiro; Ayaki, Hitoshi; Nomura, Taisei; Ikenaga, Mituo (1996): Similarity Among the \emphDrosophila (6-4) Photolyase, a Human Photolyase Homolog, and the DNA Photolyase-Blue-Light Photoreceptor Family, Science 272:109-112, Todo, 1997Todo, Takeshi; Tsuji, Hideo; Otoshi, Eriko; Hitomi, Kenichi; Kim, Sang-Tae; Ikenaga, Mituo (1997): Characterization of a human homolog of (6-4) photolyase, Mutation Research 384:195-204]. Interessanterweise fehlen den plazentalen Säugetieren aber offensichtlich Photolyasen [Kato, YearKato, Jr., Tomohisa; Todo, Takeshi; Ayaki, Hitoshi; Ishizaki, Kanji; Morita, Takashi; Mitra, Sankar; Ikenaga, Mituo (Year): Cloning of a marsupial DNA photolyase gene and the lack of related nucleotide sequences in placental mammals, Nucleic Acids Research 22:4119-4224, Yasui, 1994Yasui, Akira; Eker, Andries P.M.; Yasuhira, Shinji; Yajima, Hirohiko; Kobayashi, Takayasu; Takao, Masashi; Oikawa, Atsushi (1994): A new class of DNA photolyases present in various organisms including aplacental mammals, EMBO Journal 13:6143-6151]. Die beiden im menschlichen Genom identifizierten photolyasehomologen Gene kodieren Cryptochrome [Hsu, 1996Hsu, David S.; Zhao, Xiaodong; Zhao, Shaying; Kazantsev, Aleksey; Wang, Rui-Ping; Todo, Takeshi; Wei, Ying-Fei; Sancar, Aziz (1996): Putative Human Blue-Light Photoreceptors hCRY1 and hCRY2 Are Flavoproteins, Biochemistry 35:13871-13877]. Die Fülle der Proteine läßt sich nach ihrer Sequenzähnlichkeit und ihrer Funktion in Gruppen (Cluster) einteilen (vgl. Abb. 1). Photolyasen können anhand ihres Substrates, Cyclobutanpyrimidindimer (CPD) oder (6–4)-Photoprodukt, in CPD-Photolyasen und (6–4)-Photolyasen eingeteilt werden. Von ersteren werden wiederum zwei Klassen unterschieden. Proteine der Klasse I kommen überwiegend in prokaryotischen, jene der Klasse II in eukaryotischen Organismen vor [Yasui, 1994Yasui, Akira; Eker, Andries P.M.; Yasuhira, Shinji; Yajima, Hirohiko; Kobayashi, Takayasu; Takao, Masashi; Oikawa, Atsushi (1994): A new class of DNA photolyases present in various organisms including aplacental mammals, EMBO Journal 13:6143-6151]. Weiterhin unterscheiden sich tierische und pflanzliche Cryptochrome. Letztere besitzen eine größere Erweiterung an ihrem C-Terminus, die den tierischen Cryptochromen fehlt. Eine fünfte Gruppe, die sogenannten DASH-Cryptochrome, wurde ursprünglich als den Photolyasen ähnlicher als den Cryptochromen, aber ohne meßbare Photolyaseaktivität beschrieben [Hitomi, 2000Hitomi, Kenichi; Okamoto, Kazuhisa; Daiyasu, Hiromi; Miyashita, Hiroshi; Iwai, Shigenori; Toh, Hiroyuki; Ishiura, Masahiro; Todo, Takeshi (2000): Bacterial cryptochrome and photolyase: characterization of two photolyase-like genes of \emphSynechocystis sp. PCC6803, Nucleic Acids Research 28:2353-2362, Brudler, 2003Brudler, Ronald; Hitomi, Kenichi; Daiyasu, Hiromi; Toh, Hiroyuki; Kucho, Ken-ichi; Ishiura, Massahiro; Kaneshisa, Minoru; Roberts, Victoria A.; Todo, Takeshi; Tainer, John A.; Getzoff, Elisabeth D. (2003): Identification of a New Cryptochrome Class: Structure, Function, and Evolution, Molecular Cell 11:59-67]. Neueste Erkenntnisse [Huang, 2006Huang, Yihua; Baxter, Richard; Smith, Barbara S.; Partch, Carrie L.; Colbert, Christopher L.; Deisenhofer, Johann (2006): Crystal structure of cryptochrome 3 from \emphArabidopsis thaliana and its implications for photolyase activity, Proceedings of the National Academy of Sciences, USA 103:17701-17706, Selby, 2006Selby, Christopher; Sancar, Aziz (2006): A cryptochrome/photolyase class of enzymes with single-stranded DNA-specific photolyase activity, Proceedings of the National Academy of Sciences, USA 103:17696-17700, Pokorny, 2008Pokorny, Richard; Klar, Tobias; Hennecke, Ulrich; Carell, Thomas; Batschauer, Alfred; Essen, Lars-Oliver (2008): Recognition and repair of UV lesions in loop structures of duplex DNA by DASH-type cryptochrome, Proceedings of the National Academy of Sciences, USA 105:21023-21027] weisen darauf hin, daß zumindest manche Mitglieder dieser Gruppe Einzelstrang-DNA-Photolyasen sind.

• Kelner, Albert (1949): Effect of visible light on the recovery of \emphStreptomyces griseus conidia from ultra-violet irradiation injury., Proceedings of the National Academy of Sciences, USA 35:73-79
• Rupert, Claud S. (1960): Photoreactivation of Transforming DNA by an Enzyme from Bakers' Yeast, Journal of General Physiology 43:573-595
• Rupert, Claud S. (1962): Photoenzymatic Repair of Ultraviolet Damage in DNA I. Kinetics of the reaction, Journal of General Physiology 45:703-724
• Rupert, Claud S. (1962): Photoenzymatic Repair of Ultraviolet Damage in DNA II. Formation of an enzyme-substrate complex, Journal of General Physiology 45:725-741
• Iwatsuki, Norio; Joe, Cheol O.; Werbin, Harold (1980): Evidence That Deoxyribonucleic Acid Photolyase from Baker's Yeast Is a Flavoprotein, Biochemistry 19:1172-1176
• Sancar, Aziz; Sancar, Gwendolyn B. (1984): \emphEscherichia coli DNA Photolyase is a Flavoprotein, Journal of Molecular Biology 172:223-227
• Johnson, Jean L.; Hamm-Alvarez, Sarah; Payne, Gillian; Sancar, Gwendolyn B.; Rajagopalan, K.V.; Sancar, Aziz (1988): Identification of the second chromophore of \emphEscherichia coli and yeast DNA photolyases as 5,10-methenyltetrahydrofolate, Proceedings of the National Academy of Sciences, USA 85:2046-2050
• Eker, Andries P. M.; Kooiman, Patricia; Hessels, Johanna K. C.; Yasui, Akira (1990): DNA photoreactivating enzyme from the cyanobacterium \emphAnacystis nidulans, Journal of Biological Chemistry 265:8009-8015
• Tamada, Taro; Kitadokoro, Kengo; Higuchi, Yoshiki; Inaka, Koji; Yasui, Akira; de Ruiter, Petra E.; Eker, Andre P. M.; Miki, Kunio (1997): Crystal structure of DNA photolyase from \emphAnacystis nidulans, Nature Structural Biology 4:887-891
• Klar, Tobias; Kaiser, Gebhard; Hennecke, Ulrich; Carell, Thomas; Batschauer, Alfred; Essen, Lars-Oliver (2006): Natural and Non-natural Antenna Chromophores in the DNA Photolyase from \emphThermus Thermophilus, ChemBioChem 7:1798-1806
• Park, Hee-Won; Kim, Sang-Tae; Sancar, Aziz; Deisenhofer, Johann (1995): Crystal Structure of DNA Photolyase from \emphEscherichia coli, Science 268:1866-1872
• Ahmad, Margaret; Cashmore, Anthony R. (1993): \emphHY4 gene of \emphA. thaliana encodes a protein with characteristics of a blue-light photoreceptor, Nature 366:162-166
• Brautigam, Chad A.; Smith, Barbara S.; Ma, Zhiquan; Palnitkar, Maya; Tomchick, Diana R.; Machius, Mischa; Deisenhofer, Johann (2004): Structure of the photolyase-like domain of cryptochrome 1 from \emphArabidopsis thaliana, Proceedings of the National Academy of Sciences, USA 101:12142-12147
• Brudler, Ronald; Hitomi, Kenichi; Daiyasu, Hiromi; Toh, Hiroyuki; Kucho, Ken-ichi; Ishiura, Massahiro; Kaneshisa, Minoru; Roberts, Victoria A.; Todo, Takeshi; Tainer, John A.; Getzoff, Elisabeth D. (2003): Identification of a New Cryptochrome Class: Structure, Function, and Evolution, Molecular Cell 11:59-67
• van der Spek, P. J.; Kobayashi, K.; Bootsma, D.; Takao, M.; Eker, André P. M.; Yasui, A. (1996): Cloning, Tissue Expression, and Mapping of a Human Photolyase Homolog with Similarity to Plant Blue-Light Receptors, Genomics 37:177-182
• Todo, Takeshi; Ryo, Haruko; Yamamoto, Kazuo; Toh, Hiroyuki; Inui, Taiichiro; Ayaki, Hitoshi; Nomura, Taisei; Ikenaga, Mituo (1996): Similarity Among the \emphDrosophila (6-4) Photolyase, a Human Photolyase Homolog, and the DNA Photolyase-Blue-Light Photoreceptor Family, Science 272:109-112
• Todo, Takeshi; Tsuji, Hideo; Otoshi, Eriko; Hitomi, Kenichi; Kim, Sang-Tae; Ikenaga, Mituo (1997): Characterization of a human homolog of (6-4) photolyase, Mutation Research 384:195-204
• Kato, Jr., Tomohisa; Todo, Takeshi; Ayaki, Hitoshi; Ishizaki, Kanji; Morita, Takashi; Mitra, Sankar; Ikenaga, Mituo (Year): Cloning of a marsupial DNA photolyase gene and the lack of related nucleotide sequences in placental mammals, Nucleic Acids Research 22:4119-4224
• Yasui, Akira; Eker, Andries P.M.; Yasuhira, Shinji; Yajima, Hirohiko; Kobayashi, Takayasu; Takao, Masashi; Oikawa, Atsushi (1994): A new class of DNA photolyases present in various organisms including aplacental mammals, EMBO Journal 13:6143-6151
• Hsu, David S.; Zhao, Xiaodong; Zhao, Shaying; Kazantsev, Aleksey; Wang, Rui-Ping; Todo, Takeshi; Wei, Ying-Fei; Sancar, Aziz (1996): Putative Human Blue-Light Photoreceptors hCRY1 and hCRY2 Are Flavoproteins, Biochemistry 35:13871-13877
• Hitomi, Kenichi; Okamoto, Kazuhisa; Daiyasu, Hiromi; Miyashita, Hiroshi; Iwai, Shigenori; Toh, Hiroyuki; Ishiura, Masahiro; Todo, Takeshi (2000): Bacterial cryptochrome and photolyase: characterization of two photolyase-like genes of \emphSynechocystis sp. PCC6803, Nucleic Acids Research 28:2353-2362
• Huang, Yihua; Baxter, Richard; Smith, Barbara S.; Partch, Carrie L.; Colbert, Christopher L.; Deisenhofer, Johann (2006): Crystal structure of cryptochrome 3 from \emphArabidopsis thaliana and its implications for photolyase activity, Proceedings of the National Academy of Sciences, USA 103:17701-17706
• Selby, Christopher; Sancar, Aziz (2006): A cryptochrome/photolyase class of enzymes with single-stranded DNA-specific photolyase activity, Proceedings of the National Academy of Sciences, USA 103:17696-17700
• Pokorny, Richard; Klar, Tobias; Hennecke, Ulrich; Carell, Thomas; Batschauer, Alfred; Essen, Lars-Oliver (2008): Recognition and repair of UV lesions in loop structures of duplex DNA by DASH-type cryptochrome, Proceedings of the National Academy of Sciences, USA 105:21023-21027