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Modulation of ATR-mediated DNA damage checkpoint response by cryptochrome 1

Tae-Hong Kang1, Sun-Hee Leem

  • 1Department of Biological Science, Dong-A University, Hadan2-dong, Saha-gu, Busan 604-714, South Korea.

Nucleic Acids Research
|February 4, 2014
PubMed

Insights

Mammalian cryptochromes (Crys) regulate DNA damage checkpoints (DDC) rhythmically. Cry1 interacts with Timeless, modulating DDC capacity and influencing DNA repair during genotoxic stress.

Area of Science:

  • * Chronobiology and molecular biology.
  • * Cellular responses to DNA damage and genotoxic stress.

Background:

  • * Mammalian cryptochromes (Crys) are key circadian clock components with roles beyond timekeeping, including DNA damage responses.
  • * The DNA damage checkpoint (DDC) is crucial for maintaining genomic integrity following DNA damage.

Purpose of the Study:

  • * To investigate the role of cryptochromes (Crys) in modulating the DNA damage checkpoint (DDC) response in a time-of-day-dependent manner.
  • * To elucidate the interaction between cryptochromes (Crys) and Timeless (Tim) in the context of circadian-regulated DNA repair.

Main Methods:

  • * Utilized clock-deficient Cry1 and Cry2 double knockout (Cry(DKO)) cells and wild-type cells.
  • * Assessed DDC capacity in response to UV irradiation and cisplatin treatment at different circadian times (CT).
  • * Investigated temporal interactions between Cry1 and Tim in the nucleus using cell-based assays and analyzed protein expression (p-MCM2) in mouse liver tissue.

Main Results:

  • * Cry1 modulates the ATR-mediated DDC response through time-of-day-dependent interaction with Timeless (Tim).
  • * DDC capacity exhibits circadian rhythmicity, which is abolished in Cry(DKO) cells but can be restored by ectopic Cry1 expression.
  • * Cisplatin treatment at CT20 in mice resulted in higher p-MCM2 expression and affected DNA adduct removal compared to CT08.

Conclusions:

  • * Cryptochromes (Crys) are critical regulators of the circadian clock's influence on the DNA damage response system.
  • * The interplay between the circadian clock and DDC is essential for managing genotoxic stress in actively dividing cells.
  • * Demonstrates a direct link between circadian rhythms and DNA repair efficiency, with implications for chronotherapy.

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