6-4 photolyase differentially modulates transcription in the vertebrate circadian clock

The cryptochrome-photolyase family, a highly conserved set of flavoproteins, mediates many direct and indirect responses to sunlight. While the photolyases are light-dependent enzymes which catalyze photoreactivation repair of UV-induced DNA damage, the cryptochromes serve as circadian clock components and photoreceptors. Do DNA repair and circadian clock functions overlap in these flavoproteins? While 6–4 photolyase (6–4phr) is well-documented to repair UV-induced 6–4 photoproducts, we demonstrate that loss of 6–4phr function in fish cells and fin clips significantly attenuates circadian rhythms of period gene expression. Importantly, 6–4phr represses, as well as activates transcription directed by E-box and D-box enhancer elements respectively. Furthermore, we document physical interaction between 6–4phr and Clock1/Bmal1 at multiple domains which interferes with Clock1-Bmal1 heterodimerization. In addition, 6–4phr interacts with the D-box binding transcription factor, Tef. Thus, we reveal significant overlap between DNA repair and circadian clock functions in 6–4phr.