November 29, 2021

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Cells can efficiently repair DNA damage during human sleep

Cells can efficiently repair DNA damage during human sleep



 

Cells can efficiently repair DNA damage during human sleep. 

Revealing why you need to sleep at the cellular level: During sleep, cells efficiently repair DNA damage

 

Why do people sleep for one-third of their lives? Why do many animals sleep even when threatened by predators? How sleep benefits the brain and individual cells has always been a mystery in the scientific community. Now, the latest research from Bar Ilan University in Israel has unveiled the mystery of sleep.

 

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

 

The study explained in detail why sleep is needed at the single-cell level : In the waking state, the accumulation of DNA damage in neurons increases sleep pressure , and a protein called Parp1 perceives this increasing pressure of DNA damage. , And send out a sleep signal. During sleep, effective DNA repair is carried out in the cell , which reduces the steady-state pressure of the cell that drives the need for sleep.

 

Cells can efficiently repair DNA damage during human sleep Cells can efficiently repair DNA damage during human sleep

Illustration: when sober, DNA damage will accumulate in neurons increased fatigue, promote sleep; Parpl protein ( yellow head helmet ) perception and labeling of DNA damage cells, drive sleep, recruit repair system ( green and blue helmet ); During sleep, the DNA repair system repairs DNA damage and restarts the day.

 

 

Sleep behavior and sleep time

Sleep is accompanied by a weakened response to external stimuli and is a “fragile behavioral state.” However, during the entire evolutionary process, sleep is universal and essential to all creatures with a nervous system, including invertebrates, Drosophila, nematodes, and even jellyfish.

 

In terms of sleep, the difference between different species lies in the amount of sleep time required. For example, adult humans sleep about 7-8 hours a day, owl monkeys sleep 17 hours a day, and wild elephants that roam freely may only sleep 2 hours. These different sleep time requirements raise the basic question-what determines the specific sleep time of the species?

 

In fact, when we are awake, sleep pressure (fatigue) will continue to accumulate in the body. With the prolonged waking time, this pressure will increase and this pressure will decrease during sleep. However, what causes the internal balance pressure to rise to a certain level that makes us feel that we must sleep, and what happens at night that makes this pressure drop and prepares us to start a new day is still unclear.

 

 

Sleep and DNA damage repair

Previous studies have shown that DNA damage accumulates in neurons when awake . The Baylan University research team stated that they have observed in mice and fruit flies that wakefulness and neuronal activity induce the occurrence of DNA double-strand breaks (DSB) .

 

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

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

 

Zebrafish have absolute transparency, sleep at night, and a simple brain similar to humans. They are ideal creatures for studying this phenomenon. More importantly, the zebrafish has a perfect sleep pattern.

Its brain structure and function, as well as its DNA damage and repair system, are similar to those of mammals.

 

Cells can efficiently repair DNA damage during human sleepNeuronal activity and UV-induced DNA damage promote sleep

 

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

The results show that with the increase of DNA damage, the need for sleep will also increase .

At a certain moment, the accumulation of DNA damage reaches a maximum threshold and increases sleep pressure, so that the urge to sleep is triggered, and zebrafish go Go to sleep.

The subsequent sleep promotes DNA repair, thereby reducing DNA damage.

 

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

 

Cells can efficiently repair DNA damage during human sleepAfter sleep and DNA damage are induced, the repair activity of Rad52 and ku80 increases

 

After determining that accumulated DNA damage is the driving force behind the sleep process, the researchers wanted to further determine the minimum amount of time that zebrafish need to sleep.

Like humans, zebrafish are also very sensitive to light interference, so they can use light to interrupt sleep, thereby controlling zebrafish’s sleep time.

 

Zebrafish need 6 hours of sleep to restore neuronal DNA damage to normal

 

The results of the study show that six hours of sleep a night is sufficient to reduce DNA damage in zebrafish.

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

The research team further pointed out that there is a strong positive correlation between the level of neuronal DNA damage and total sleep time, which indicates that the degree of DNA damage can predict the total sleep time required for repair.

 

 

Parp1 promotes brain sleep

If sleep is to repair DNA damage, then another question arises- what mechanism in the brain tells us that we need sleep to promote efficient DNA repair?

 

In this regard, the research team pointed out 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.

The activation of the DDR protein may send a sleep signal to the organism to increase the dynamics of the chromosome and make the effective assembly of the repair protein possible.

 

Parp1 regulates sleep caused by DNA damage

 

The researchers focused their attention on a protein called Parp1 , which is part of the DNA damage repair system and responds to single-stranded and double-stranded DNA breaks. Parp1 marks the DNA damage site in the cell and calls all relevant systems to eliminate DNA damage.

 

The research team found that the aggregation of Parp1 at DNA break sites increased during wakefulness and decreased during sleep.

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

On the contrary, knockdown of Parp1 blocked the signal for DNA damage repair, which resulted in a very interesting result: these zebrafish did not fully realize that they were tired, they did not go to sleep, and did not perform DNA damage repair.

 

In order to enhance the persuasiveness 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 results of the study showed that, as they had seen in zebrafish, the duration and quality of non-rapid eye movement sleep (NREM) in Parp1 knockdown mice was reduced.

 

Cellular mechanism of sleep homeostasis regulation

 

The corresponding author of this study, Dr. Lior Appelbaum , pointed out that when neurons are awake, the maintenance process of DNA repair may not be effective enough, so an offline sleep period is required to reduce information input to the brain. The Parp1 pathway can send a signal to the brain- for DNA repair, the brain needs sleep .

 

 


Conclusion:

All in all, this study uses cell and nuclear marker imaging, coupled with zebrafish and mouse behavior monitoring, to confirm that neuronal DNA damage may be an important cause of sleep -that is, the brain needs sleep to promote DNA repair activities .

In the process, Parp1 is an important sleep timer. When DNA damage reaches a certain level, it will issue sleep instructions to the brain to promote the sleep process.

 

Schematic diagram of this study

 

The research team said that these findings will help understand the causal link between wakefulness and sleep, and may guide the treatment of aging and neurodegenerative diseases.

 

 

 

Reference:
https://doi.org/10.1016/j.molcel.2021.10.026
https://www.genengnews.com/news/study-unpicks-what-drives-the-need-for-sleep-at-the-cellular-level/

Cells can efficiently repair DNA damage during human sleep. 

(source:internet, reference only)


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