The DASH-type Cryptochrome from the Fungus Mucor circinelloides Is a Canonical CPD-Photolyase

• Published in: Current biology 2020-11, Vol.30 (22), p.4483-4490.e4
• Main Authors: Navarro, Eusebio, Niemann, Nils, Kock, Dennis, Dadaeva, Tamila, Gutiérrez, Gabriel, Engelsdorf, Timo, Kiontke, Stephan, Corrochano, Luis M., Batschauer, Alfred, Garre, Victoriano
• Format: Article
• Language: English
• Subjects: cryptochrome; cyclobutane pyrimidine dimer; DNA repair; Mucor; photolyase
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2020.08.051

Cryptochromes and photolyases are blue-light photoreceptors and DNA-repair enzymes, respectively, with conserved domains and a common ancestry [1–3]. Photolyases use UV-A and blue light to repair lesions in DNA caused by UV radiation, photoreactivation, although cryptochromes have specialized roles ranging from the regulation of photomorphogenesis in plants, to clock function in animals [4–7]. A group of cryptochromes (cry-DASH) [8] from bacteria, plants, and animals has been shown to repair in vitro cyclobutane pyrimidine dimers (CPDs) in single-stranded DNA (ssDNA), but not in double-stranded DNA (dsDNA) [9]. Cry-DASH are evolutionary related to 6-4 photolyases and animal cryptochromes, but their biological role has remained elusive. The analysis of several crystal structures of members of the cryptochrome and photolyase family (CPF) allowed the identification of structural and functional similarities between photolyases and cryptochromes [8, 10–12] and led to the proposal that the absence of dsDNA repair activity in cry-DASH is due to the lack of an efficient flipping of the lesion into the catalytic pocket [13]. However, in the fungus Phycomyces blakesleeanus, cry-DASH has been shown to be capable of repairing CPD lesions in dsDNA as a bona fide photolyase [14]. Here, we show that cry-DASH of a related fungus, Mucor circinelloides, not only repairs CPDs in dsDNA in vitro but is the enzyme responsible for photoreactivation in vivo. A structural model of the M. circinelloides cry-DASH suggests that the capacity to repair lesions in dsDNA is an evolutionary adaptation from an ancestor that only had the capacity to repair lesions in ssDNA. •The cryptochrome DASH from Mucor circinelloides binds the cofactors FAD and 5,10-MTHF•Cryptochrome DASH from Mucor repairs thymine dimers in double-stranded DNA•Cryptochrome DASH from Mucor is responsible for photoreactivation in vivo Navarro et al. show that cry-DASH from the fungus Mucor circinelloides repairs DNA lesions in dsDNA and is the enzyme responsible for light-dependent DNA repair in vivo. The authors suggest that the capacity of Mucor cry-DASH to repair lesions in dsDNA is an evolutionary adaptation from an ancestor that only was able to repair lesions in ssDNA.