DNA repair enzyme affects daily rhythms

Jim Crocker
13th December, 2025

DNA repair enzyme affects daily rhythms

NanoBiT (a, b, e) and yeast two-hybrid (c, d, f) assays demonstrate that the DNA repair protein 6-4phr physically interacts with the core circadian clock regulators Clock1a and Bmal1a, as well as the D-box binding transcription factor Tefb.

Image adapted from: Li et al. / CC BY (Source)

Key Findings

  • Fish cells lacking the 6–4phr protein show disrupted daily rhythms in gene expression
  • The 6–4phr protein regulates clock genes by both suppressing and activating gene transcription
  • 6–4phr directly interacts with key clock proteins, interfering with their normal function
Our bodies operate on roughly 24-hour cycles, known as circadian rhythms, influencing everything from sleep patterns to hormone release. These rhythms are governed by internal ‘clocks’ present in nearly all living organisms[1]. Disruptions to these clocks have been linked to a variety of health problems, including cardiovascular disease and neurodegenerative disorders[2][3]. A key question in this field is understanding how these clocks are influenced by external factors, and how they, in turn, affect cellular processes. Recent research from the Karlsruhe Institute of Technology, Osaka University, and Harvard Medical School investigated a potential link between DNA repair mechanisms and these internal clocks, specifically focusing on a protein family called cryptochrome-photolyase. The study centered on 6–4 photolyase (6–4phr), an enzyme known to repair DNA damage caused by ultraviolet (UV) light. While its role in DNA repair is well-established, its connection to the circadian clock was less clear. Researchers hypothesized that 6–4phr might have a dual function, participating in both DNA repair and the regulation of circadian rhythms. To test this, they examined the effects of removing 6–4phr function in fish cells and fin clips. The results showed a significant weakening of the circadian rhythms in the expression of ‘period’ genes – genes central to the clock mechanism. This suggests that 6–4phr is not just involved in fixing DNA, but also in maintaining the timing of the internal clock. Further investigation revealed that 6–4phr directly influences gene transcription, both suppressing it at certain DNA sequences (E-box elements) and activating it at others (D-box elements). This ability to both promote and inhibit gene expression is crucial for the clock's function, which relies on a feedback loop of gene activation and repression. The team then discovered a physical interaction between 6–4phr and two key proteins of the clock, Clock1 and Bmal1. This interaction interfered with the ability of Clock1 and Bmal1 to pair up (heterodimerization), a necessary step for their function in regulating gene expression. Additionally, 6–4phr was found to interact with Tef, a transcription factor that binds to D-box elements. These findings highlight a significant overlap between DNA repair and circadian clock functions within 6–4phr. The study builds upon previous work showing that DNA damage can, in fact, reset the circadian clock[2]. This earlier research demonstrated that ionizing radiation, ultraviolet light, and other damaging agents could shift the timing of internal rhythms, and that this process involved a signaling pathway called ATM. The current study expands on this by identifying a specific protein – 6–4phr – that appears to be a key mediator of this effect. It suggests that the clock isn't simply affected by DNA damage, but actively responds to it through the action of 6–4phr. Interestingly, this research also connects to observations about neurodegenerative diseases[4]. These diseases often involve disruptions to sleep-wake cycles and the accumulation of misfolded proteins. The study’s findings suggest that 6–4phr, by influencing both DNA repair and circadian rhythms, could play a role in the protein aggregation processes characteristic of these conditions. While this link requires further investigation, it points to a potential common pathway underlying these complex disorders. The discovery that 6–4phr interacts with components of the circadian clock, and influences gene expression, provides a new avenue for understanding how cellular processes are timed and regulated, and how disruptions to this timing can lead to disease.

GeneticsBiochemEvolution

References

Main Study

1) 6-4 photolyase differentially modulates transcription in the vertebrate circadian clock

Published 12th December, 2025

https://doi.org/10.1371/journal.pgen.1011971

Related Studies

2) Phase resetting of the mammalian circadian clock by DNA damage.

https://doi.org/10.1016/j.cub.2008.01.047

3) Recent advances in circadian rhythms in cardiovascular system.

https://doi.org/10.3389/fphar.2015.00071

4) Circadian clocks and neurodegenerative diseases: time to aggregate?

https://doi.org/10.1016/j.conb.2013.05.004


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