Structure and Function of Animal Cryptochromes

Abstract

Cryptochrome (CRY) is a photolyase-like flavoprotein with no DNA-repair activity but with known or presumed blue-light receptor function. Animal CRYs have DNA-binding and autokinase activities, and their flavin cofactor is reduced by photoinduced electron transfer. In Drosophila, CRY is a major circadian photoreceptor, and in mammals, the two CRY proteins are core components of the molecular clock and potential circadian photoreceptors. In mammals, CRYs participate in cell cycle regulation and the cellular response to DNA damage by controlling the expression of some cell cycle genes and by directly interacting with checkpoint proteins. in response to blue light (Koornneef et al. 1980), was isolated and sequenced, it revealed high sequence homology with Escherichia coli photolyase, and hence, it was in retrospect, correctly speculated that HY4 encoded a blue light photoreceptor and not a signal transducer involved in blue light response (Ahmad and Cashmore 1993). Later, this protein was named cryptochrome 1 (Lin et al. 1995, and a second Arabidopsis protein that has high homology with CRY1 identified by genomics was named CRY2 . The role of CRY in Arabidopsis growth (CRY1) and differentiation (CRY2) was well established by 1995 (see Guo et al. 1998). However, as late as 1997, it was thought that CRY had no role in circadian photoreception in plants (Millar and Kay 1997).The first report implicating CRY in the circadian clock of any organism, plant or animal, came about from the study of DNA repair, in particular, the repair of UV damage in humans by photolyase. This issue had been controversial for nearly 25 years when Li et al. (1993) conducted an exhaustive study with a highly specific and sensitive assay, concluding that humans, like all placental mammals, lacked photolyase (Li et al. 1993). However, a 1995 release of a human expressed sequence tag (EST) list contained a "photolyase ortholog" entry (Adams et al. 1995). In light of this finding and the discovery of a photolyase in Drosophila and rattlesnake (Todo et al. 1993Kim et al. 1996) that repairs the minor UV-induced lesion, the (6-4) photoproduct, in contrast to the classic photolyase that repairs cyclobutane pyrimidine dimers (CPDs), the earlier conclusion regarding the lack of photolyase in humans needed reevaluation. This was done by Hsu et al. (1996) who, in addition to the "photolyase ortholog" in public databases, discovered a second human photolyase gene. Human cells expressing both genes and recombinant proteins encoded by both genes were tested for CPD and (6-4) photolyase activities and were found to lack both. Moreover, the proteins encoded by these genes, like most photolyases (Johnson et al. 1988) and Arabidopsis CRY (Lin et al. 1995; Malhorta et al. 1995), contained FAD (flavin-adenine dinucleotide) and a pterin cofactor. Therefore, it was concluded that these proteins were not repair enzymes but that, like Arabidopsis CRYs, they performed non-repair-related blue light functions and were named human CRY1 and 2 (Hsu et al. 1996). In humans ...

Cryptochrome expression in the eye of migratory birds depends on their migratory status

“…These molecules have been shown to play a crucial role in the circadian clock, with differences between species (Oztürk et al, 2007). For instance, in some invertebrates, CRY acts as circadian photoreceptor (Busza et al, 2004), whereas in other invertebrates and vertebrates it plays a role as transcriptional repressor (Sancar, 2004;Zhu et al, 2005).…”

Animal Type 1 Cryptochromes

“…Light exposure leads to photoreduction through the Trp triad to either FADH ⅐ (plant CRYs) or FAD . (Type 1 CRYs) forms of CRYs, which are the signaling forms (29,30). In the second model, which we refer to as the "photolyase model," it is proposed that the flavin cofactor is actually in the form of FAD .…”

“…These models differ fundamentally in the presumed redox status of the flavin cofactor in the dark phase. In one model, which we have designated the "phototropin model" (29), it is assumed that CRYs contain FAD ox in ground state. Light exposure leads to photoreduction through the Trp triad to either FADH ⅐ (plant CRYs) or FAD .…”

Structure and Function of Photolyase and in Vivo Enzymology: 50th Anniversary

“…Currently, any protein with sequence homology to photolyase but with no repair function is called cryptochrome and is presumed to be a photosensory pigment (37)(38)(39)(40)(41). In A. thaliana, it has been shown conclusively that AtCRY1 and AtCRY2 function as blue-light photoreceptors (9).…”