Successful DNA replication in cyanobacteria depends on the circadian clock

STATUE: DNA replication cycles are linked to the circadian clock and interruptions can lead to incomplete chromosomes. view more

Credit: Image courtesy of Yi Liao.

A new study from the University of Chicago has found that the photosynthetic bacteria Synechococcus elongatus uses a circadian clock to accurately time DNA replication, and that interrupting this circadian rhythm prevents replication and leaves chromosomes unfinished overnight. The results, published online May 10 in Proceedings of the National Academy of the Sciences, have implications for understanding how interrupted circadian rhythms can affect human health.

Circadian rhythms are the internal 24-hour clock common to most organisms on Earth and regulate a variety of biological functions, including sleep / wake cycles, hormone production, digestion and body temperature. In humans, circadian rhythm disturbances – such as shift work or experiencing frequent jet lag – have been linked to a range of health problems, including obesity, cardiovascular and immune disorders, mood disorders, and even cancer.

“In most of the species we have studied, it is bad for the animal’s health if the circadian rhythm is disrupted or permanently changed, but no one has really been able to explain what goes wrong if your clock is in the wrong state all the time , said senior author Michael Rust, PhD, associate professor of molecular genetics and cell biology at UChicago. “This cyanobacterial system is exciting because it gives us the opportunity to answer these mechanistic questions about how circadian rhythms contribute to the health of an organism.”

Despite the large evolutionary gap between humans and cyanobacteria, these tiny organisms can provide insight into crucial cellular functions such as DNA replication. “The evidence suggests that circadian rhythms have evolved multiple times between different species, so there must be something very basic and important shared by these different species,” said lead author Yi Liao, a postdoctoral researcher in Rust’s lab. “DNA replication is also a fundamental process, shared by species, which gave us an indication that it can be regulated by this clock.”

The researchers were particularly interested in studying this process because of its long duration. “Some things are better to do during the day, such as photosynthesis, while others are better at night, such as fixing nitrogen,” said Rust. “But DNA replication takes three to four hours to replicate the entire genome, so there is a fundamental need to predict the future. You commit to doing this and you don’t know what the conditions will look like a few hours later. It seemed like maybe this process would use circadian rhythms to ‘predict’ the right time to start replication, to make sure it ends during an optimal time period. ”

Combining time-lapse fluorescence microscopy, mathematical modeling, molecular genetics and biochemical approaches, Liao and Rust were able to track the initiation, completion, and failure of DNA replication in bacteria exposed to various illumination patterns, including constant light, normal light / dark. cycles and cycles with unexpected periods of darkness.

They found that the circadian clock creates rhythms in DNA replication, even when there are no environmental factors, such as the rising and setting sun. DNA replication usually starts when the clock state corresponds to morning and is suppressed when the clock predicts the arrival of night. However, when the bacteria’s internal clock predicts morning, but the external environment unexpectedly darkens, the ongoing replication cannot be completed; the replication machine is disassembled, leaving cells with incomplete chromosomes.

“A lot of things are regulated by the circadian clock, but it’s striking that it’s so important to DNA replication,” said Rust. “If the clock is in the wrong state, it is the difference between the replication event completing or the replication equipment completely disintegrating.”

These results, Liao says, raise even more questions. “What is the fate of these unfinished chromosomes? Does this lead to mutations?” he said. “Perhaps this is a major driving force behind the evolution of the circadian clock – you want to avoid damaged DNA and unfinished chromosomes, so the clock has evolved several times in history to prevent those things from happening.”

In a post-Industrial Revolution society, surrounded by artificial light that can be turned on and off at will, these results can have implications for the impact of circadian rhythms on human health and why extensive disruptions can be so damaging.

“One question we have yet to answer is whether or not this failure to complete DNA replication leads to mutation and genomic instability,” Rust said. Organisms can sometimes experience unexpected darkness, but their clocks receive very strong signals from the cycle of the rising and setting sun. In humans, where we can control the lighting of our environment and ignore the sun, we know that there are changes in the sun circadian rhythm and we know it causes problems, but it is not clear where those problems come from. We are trying to put our finger on a molecular mechanism for what could be the biggest problem if your circadian clock is in the wrong position is wrong. ‘

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The study “The Circadian Clock Ensures Successful DNA Replication in Cyanobacteria” was supported by the Howard Hughes Medical Institute (Simons Faculty Scholar Prize) and the NIH (R01-GM107369).

About the University of Chicago Medicine & Biological Sciences

The University of Chicago Medicine, with a history dating back to 1927, is one of the nation’s premier academic health systems. It unites the missions of the University of Chicago Medical Center, Pritzker School of Medicine and the Biological Sciences Division. Twelve Nobel laureates in physiology or medicine are affiliated with the University of Chicago Medicine. Hyde Park’s main campus is home to the Center for Care and Discovery, Bernard Mitchell Hospital, Comer Children’s Hospital, and the Duchossois Center for Advanced Medicine. It also has outpatient facilities in Orland Park, South Loop and River East, as well as connections and partnerships that create a regional network of care. UChicago Medicine offers a full range of specialist adult and pediatric care services through more than 40 institutions and centers, including an NCI-designated Comprehensive Cancer Center. Along with the Harvey-based Ingalls Memorial, UChicago Medicine has 1,296 licensed beds, nearly 1,300 treating physicians, more than 2,800 nurses, and approximately 970 residents and fellows.

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