The research, published in the journal Nature Communications, found that circadian clock proteins REV-ERBα (and REV-ERBβ) are key regulators of DNA repair, specifically through the non-homologous end joining (NHEJ) pathway.
"Circadian rhythms are crucial for many aspects of human physiology, including sleep-wake cycles, hormone regulation, and metabolism," said lead author Richard Schwartzentruber, a graduate student in the lab of Northwestern's Dr. Joseph Takahashi, Charles E. and Susan T. Harris Professor in the Department of Neurobiology and director of the Center for Sleep and Circadian Biology.
"Our findings reveal a completely unexpected connection between circadian rhythms and the body's response to DNA-damaging agents such as UV light, which is the main environmental cause of skin cancer," he said.
Circadian rhythms are internal body clocks that regulate many physiological and behavioral processes over approximately 24-hour cycles. The disruptions to these internal clocks caused by modern life, such as shift work and jet lag, have been linked to increased cancer risk in humans.
For more than 40 years, researchers have known that disrupted circadian rhythms, in the form of mutations or altered function of circadian clock genes, are associated with DNA repair deficiencies and increased cancer risk. However, the underlying reasons were not clear.
"Our research was initially inspired by the connection between disrupted circadian rhythms and cancer," Schwartzentruber said. "We wanted to understand how the loss of circadian clock function, specifically of the REV-ERB proteins, could lead to increased levels of DNA damage and promote skin cancer formation in animal models."
To investigate this, the researchers used mice with specific circadian clock gene mutations that mimic conditions observed in human cancers. They found that mice lacking either REV-ERBα or REV-ERBβ had impaired DNA repair and increased sensitivity to DNA-damaging agents like ultraviolet (UV) radiation, which is a known cause of skin cancer.
Further analysis revealed that the decreased DNA repair capacity in REV-ERB-deficient mice was due to the dysregulation of the NHEJ pathway, a critical system in the cell that repairs damaged DNA.
To better understand the cellular and molecular mechanisms underlying this connection, the researchers then isolated and studied skin cells from the mice. They utilized advanced imaging tools and molecular biology techniques to measure DNA damage and repair in these cells.
"We found that REV-ERBα is specifically recruited to sites of DNA damage in skin cells," Schwartzentruber said. "REV-ERBα appears to play an essential role in promoting the DNA repair process in response to DNA-damaging agents."
The researchers validated these findings in human skin cells as well, demonstrating that the DNA repair-promoting function of REV-ERB proteins is conserved between mice and humans.
"Our study provides the first molecular evidence that REV-ERB proteins are critical for DNA repair in the skin," Schwartzentruber said. "We believe this could explain the link between disrupted circadian rhythms and increased cancer risk observed in humans."
Understanding the role of circadian clock proteins in DNA repair could lead to new strategies to mitigate the effects of disrupted circadian rhythms or the development of DNA repair-promoting drugs modeled after REV-ERBs.
"These findings reveal an important new dimension of circadian biology and suggest potential therapeutic avenues for promoting DNA repair and preventing skin cancer," Takahashi said.
