July 23, 2024

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DNA damaged during the day must be repaired during sleep

DNA damaged during the day must be repaired during sleep


DNA damaged during the day must be repaired during sleep, this is why you need a good sleep.


Why do people spend a third of their lives sleeping? Why do many animals sleep even when threatened by predators? How sleep benefits the brain and individual cells has long been a mystery in the scientific community.

Now, new research from Israel’s Bar-Ilan University has unraveled the mystery of sleep.


On November 18, 2021, researchers from Bar-Ilan University in Israel published a research paper entitled: Parp1 promotes sleep, which enhances DNA repair in neurons in Molecular Cell , a sub-journal of Cell .


The study provides a detailed explanation of why sleep is needed at the single-cell level : During wakefulness, the accumulation of DNA damage in neurons increases sleep stress , and a protein called Parp1 senses this increasing DNA damage stress , and issue a sleep signal.

During sleep, efficient DNA repair takes place within cells , reducing the cellular homeostatic stress that drives the need for sleep.


DNA damaged during the day must be repaired during sleep DNA damaged during the day must be repaired during sleep
Illustration: DNA damage accumulation in neurons during wakefulness increases fatigue and promotes sleep; Parp1 protein ( yellow helmet ) senses and marks DNA damage in cells, drives sleep, and recruits repair systems ( green and blue helmets ) ); during sleep, the DNA repair system repairs DNA damage and starts the day over.


Sleep behavior and sleep duration


Sleep is a “vulnerable behavioral state” accompanied by a diminished response to external stimuli. However, sleep has been common and essential to all organisms with nervous systems throughout evolution, including invertebrates, fruit flies, nematodes, and even jellyfish.


When it comes to sleep, the difference between species is the amount of sleep required.

For example, an adult human sleeps about 7-8 hours a day, an owl monkey sleeps 17 hours a day, and a free-roaming wild elephant may only sleep 2 hours.

These varying sleep duration requirements raise fundamental questions – what determines species-specific sleep duration?


In fact, sleep stress (fatigue) builds up in the body while we’re awake, increases with time awake, and decreases during sleep.

But exactly what causes homeostatic pressure to rise to the point where we feel compelled to sleep, and what happens at night to bring that pressure down and get us ready to start the day, is unclear.



Sleep and DNA damage repair

Previous research has shown that DNA damage accumulates in neurons during waking hours .

The Bar-Ilan University team said they observed in mice and flies that wakefulness and neuronal activity induce DNA double-strand breaks (DSBs) .


The research team conducted a series of experiments to try to determine whether the accumulation of DNA damage might be a driver of homeostatic stress and subsequent sleep states.

Scientists first turned to the zebrafish as an animal model they could use to try to identify cellular sleep drivers and understand the role of sleep in restoring nuclear homeostasis at the level of individual neurons.


With absolute transparency, nocturnal sleep, and a simple human-like brain, zebrafish are ideal organisms to study this phenomenon.

What’s more, the zebrafish has a well-established sleep pattern, and its brain structure and function, as well as its DNA damage and repair systems, are similar to those of mammals.


DNA damaged during the day must be repaired during sleep
Neuronal activity and UV-induced DNA damage promote sleep


Using ultraviolet radiation, pharmacological interventions and optogenetics, the researchers induced DNA damage in zebrafish to examine how it affected their sleep.

The results show that as DNA damage increases, so does the need for sleep , and at a certain point the accumulation of DNA damage reaches a maximum threshold and increases sleep pressure so much that the urge to sleep is triggered, and the zebrafish goes Go to sleep.

Subsequent sleep promotes DNA repair, which reduces DNA damage.


“Our experiments show that sleep increases the aggregation of Rad52 and Ku80 repair proteins in neurons, which normalizes the level of DNA damage,” the authors said.


DNA damaged during the day must be repaired during sleep
Increased repair activity of Rad52 and ku80 after sleep and DNA damage induction


Having established that accumulated DNA damage is the force driving the sleep process, the researchers wanted to further determine the minimum amount of time zebrafish needed to sleep.

Like humans, zebrafish are sensitive to the disturbance of light, so sleep can be controlled by interrupting sleep with light.


Zebrafish need 6 hours of sleep enough to normalize neuronal DNA damage


The findings suggest that six hours of sleep per night is sufficient to reduce DNA damage in zebrafish.

And, surprisingly, DNA damage was not sufficiently reduced after sleeping less than 6 hours, and the zebrafish continued to sleep even during the day.

The team further noted that there was a strong positive correlation between the level of DNA damage in neurons and total sleep time, suggesting that the degree of DNA damage could predict the total sleep time required for repair.



Parp1 promotes sleep in the brain

If sleep is to repair DNA damage, then another question arises – what mechanism in the brain tells us that sleep is required for efficient DNA repair?


In this regard, the team noted that sleep promotes the activity of the DNA damage repair (DDR) signaling pathway, which includes DNA damage sensors, signal transducers, and effector proteins required for repair.

Activation of DDR proteins may signal sleep to the organism to increase chromosomal dynamics and enable efficient assembly of repair proteins.


Parp1 regulates sleep induced by DNA damage


The researchers focused on a protein called Parp1 , which is part of the DNA damage repair system and responds to single- and double-stranded DNA breaks.

Parp1 marks DNA damage sites in cells and summons all relevant systems to clear DNA damage.


The team found that Parp1 aggregation at DNA breakage sites increases during wakefulness and decreases during sleep.

Through genetic and pharmacological manipulation, overexpression and knockdown of the Parp1 gene revealed that Parp1 overexpression promotes sleep and also increases sleep-dependent repair.

Conversely, knockdown of Parp1 blocked DNA damage repair signaling, with a very interesting result: The zebrafish didn’t fully realize they were tired, so they didn’t go to sleep and didn’t perform DNA damage repair.


To enhance the convincingness of the study, the research team further conducted similar experiments in mice—using EEG to further test the role of Parp1 in regulating sleep in mice.

The findings showed that, as they saw in zebrafish, Parp1 knockdown mice had reduced non-rapid eye movement (NREM) sleep duration and quality.


Cellular mechanisms of sleep homeostasis regulation


The study’s corresponding author , Dr. Lior Appelbaum , pointed out that the maintenance process of DNA repair may not be efficient enough when neurons are awake, so an offline sleep period is required, reducing the input of information to the brain. The Parp1 pathway signals the brain that it needs sleep for DNA repair .



Altogether, this study, through imaging of cellular and nuclear markers, coupled with behavioral monitoring in zebrafish and mice, confirms that neuronal DNA damage may be an important contributor to sleep — the brain ‘s need for sleep to fuel DNA repair During the process, Parp1 is an important sleep timer.

When DNA damage reaches a certain level, it sends sleep instructions to the brain and promotes the sleep process.


Schematic diagram of this study


The findings will help understand the causal link between wakefulness and sleep, and may guide treatments for aging and neurodegenerative diseases, the team said.




DNA damaged during the day must be repaired during sleep

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