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.