Cryptochrome

Cryptochromes were first identified in Arabidopsis thaliana in 1993 by Margaret Ahmad and Anthony Cashmore, who named them for their cryptic nature and blue-light absorption.¹ They belong to the cryptochrome/photolyase family (CPF), which includes DNA photolyases that repair UV damage. Cryptochromes are classified into two types: plant cryptochromes (e.g., CRY1, CRY2) and animal cryptochromes (e.g., Drosophila CRY, mammalian CRY1/CRY2). Animal cryptochromes are further divided into light-responsive (type 1) and light-insensitive (type 2) forms, the latter acting as core components of the circadian clock.²

Cryptochromes contain a noncovalently bound flavin adenine dinucleotide (FAD) chromophore and an N-terminal photolyase homology region (PHR) domain. Light absorption induces electron transfer to FAD, leading to a signaling state that triggers conformational changes. In plants, the C-terminal domain (CCE) is essential for signaling, and phosphorylation regulates activity. In animals, the PHR domain interacts with clock proteins such as PER and TIM. The photoreduction of FAD is a key step, and the radical pair mechanism is proposed for magnetoreception.³

In mammals, cryptochromes (CRY1 and CRY2) are transcriptional repressors in the negative feedback loop of the circadian clock. They form a complex with Period proteins (PER1/PER2) and inhibit the CLOCK-BMAL1 transcription factor, generating ~24-hour rhythms. Mutations in CRY1 or CRY2 disrupt circadian behavior in mice and are linked to familial advanced sleep phase syndrome in humans.⁴ In Drosophila, CRY acts as a photoreceptor that resets the clock in response to light, whereas in mammals, light input is mediated by the eyes via the suprachiasmatic nucleus.

Cryptochromes are the leading candidate for the magnetic sense in animals. The radical pair mechanism posits that photoexcitation of FAD produces radical pairs whose spin state is influenced by Earth's magnetic field, altering protein conformation and signaling. Evidence includes behavioral studies in fruit flies, robins, and mole-rats, as well as electrophysiological responses in pigeon retinal neurons. However, the precise mechanism and physiological relevance remain debated, with some studies questioning the role of cryptochromes in mammals.⁵

Beyond circadian rhythms and magnetoreception, cryptochromes are involved in plant growth and development, including hypocotyl elongation, flowering time, and stomatal opening. They also function in DNA damage repair in some organisms, although they lack photolyase activity. In insects, cryptochromes may mediate UV-A sensitivity. A notable lesser-known fact is that cryptochromes are expressed in the retina and may play a role in light-dependent magnetic orientation in migratory birds. Additionally, cryptochromes have been implicated in the regulation of reactive oxygen species and in cancer biology, as they influence cell proliferation and DNA repair pathways.⁶

Flavoprotein

A protein that contains a flavin cofactor, such as FAD or FMN.

Photolyase

A DNA repair enzyme that uses light energy to repair UV-induced damage.

Circadian rhythm

An endogenous ~24-hour biological cycle.

Radical pair

A pair of molecules with unpaired electrons whose spins are correlated.

Suprachiasmatic nucleus

The brain region that serves as the master circadian clock in mammals.