In order to learn faster, brain cells destroy their DNA
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This discovery not only provides insight into the nature of brain plasticity. It also shows that DNA breaks may be a routine and important part of normal cellular processes-this has an impact on how scientists perceive aging and disease and how they deal with genomic events, which they usually think are just bad luck.
Another reason why this discovery is surprising is that DNA double-strand breaks are a particularly dangerous gene damage, which is related to cancer, neurodegeneration and aging. DNA double-strand break refers to the two tracks of a spiral ladder being cut at the same position in the genome. Since there is no complete “template” left to guide the reconnection of the double-strand, it is more difficult for cells to repair double-strand breaks than to repair other types of DNA damage.
However, it has long been recognized that DNA breaks sometimes play a constructive role. When a cell divides, a double-strand break allows the normal process of genetic recombination between chromosomes. In the developing immune system, they recombine DNA fragments and produce multiple antibodies. Double-strand breaks are also related to neuron development and helping to turn on certain genes. Nevertheless, these functions seem to be the exception, and double-strand breaks are accidental and unwelcome rules.
But there was a turning point in 2015. Neuroscientist Li-Huei Tsai, director of the MIT Picauer Institute for Learning and Memory, and her colleagues are tracking previous studies linking Alzheimer’s disease to the accumulation of neuronal double-strand breaks. To their surprise, the researchers found that stimulating cultured neurons triggers double-strand breaks in their DNA, and this break rapidly increases the expression of 12 fast-reacting genes related to synaptic activity in learning and memory .
Double-strand breaks seem to be essential for regulating gene activity, and gene activity is essential for neuron function. Tsai and her collaborators on the paper speculate that the break essentially releases enzymes that stick to the twisted DNA fragments, allowing them to quickly transcribe nearby related genes. But Tsai said that this idea has been questioned a lot. “It’s just hard to imagine that double-strand breaks are actually physiologically important.”
However, Paul Marshall, a postdoctoral researcher at the University of Queensland in Australia, and his colleagues decided to continue studying this discovery. Their research results published in 2019 confirm and extend the observations of the Tsai team. The results showed that DNA breaks triggered two waves of enhanced gene transcription, one wave was immediate and the other wave was a few hours later.
Marshall and his colleagues proposed a two-step mechanism to explain this phenomenon: When DNA breaks, some enzyme molecules are released for transcription, and the break position is also marked by a methyl group. This is A so-called epigenetic mark. Later, when the damaged DNA starts to be repaired, the marker is removed – in the process, more enzymes will overflow and the second round of transcription will begin.
Marshall said: “The double-strand break is not only a trigger, it also becomes a marker, and this marker itself has a function in regulating and guiding the mechanism to reach that location.”
p >Since then, other studies have proved similar results. An article published last year believed that double-strand breaks are not only related to the formation of fear memories, but also related to their memories.
Now, in a study published in “PLOS ONE” last month, Tsai and her colleagues showed that this counterintuitive gene expression mechanism may be widespread in the brain. This time, instead of using cultured neurons, they looked at cells in the brains of living mice that are learning to associate the environment with electric shocks. When the research team mapped the genes for double-strand breaks in the prefrontal cortex and hippocampus of mice subjected to electric shocks, they found that nearly hundreds of genes were broken, many of which are related to synaptic processes related to memory.
However, it is also interesting that there were some double-strand breaks in the neurons of the mice that were not shocked. Timothy Jarome, a neuroscientist at Virginia Institute of Technology and State University, did not participate in the study, but did related work. He pointed out: “These rests are normal in the brain. I think this is the most surprising aspect, because it shows that it is happening all the time.”
To further support this conclusion, the scientists also Double-strand breaks are observed in non-neuronal brain cells called glial cells. In this cell, glial cells regulate different kinds of genes. This finding hints at the role of glial cells in the formation and storage of memory. It also suggests that DNA fragmentation may be a regulatory mechanism for many other cell types. Jarome said: “This mechanism may be more extensive than we thought.”
But even if DNA damage is a particularly fast method of inducing key gene expression, whether it is for memory consolidation or for other cells Function, it also has risks. If double-strand breaks occur in the same location again and again and are not properly repaired, genetic information may be lost. In addition, “this type of gene regulation may make neurons vulnerable to genome damage, especially under conditions of aging and neurotoxicity,” Tsai said.
“It is interesting that it is used so frequently in the brain,” said Bruce Yankner, a neurologist and geneticist at Harvard Medical School, “and cells can be unaffected by it, without Cause devastating damage.” He also did not participate in this new work.
This may be because the repair process is effective, but this situation may change with age. Tsai, Marshall, and others are studying whether and how this can be a neurodegenerative mechanism for diseases such as Alzheimer’s disease. Yankner said it may also cause glial cancer or post-traumatic stress disorder. If double-strand breaks regulate gene activity in cells outside the nervous system, the destruction of this mechanism may also lead to, for example, muscle loss or heart disease.
With a better understanding of the details and uses of this mechanism in the body, they may eventually guide the development of new medical treatments. Marshall pointed out that, at least, considering the importance of double-strand breaks in the basic memory process, merely trying to prevent double-strand breaks may not be the right approach.
But this work also shows that we need to stop thinking about the genome in a static way and start to think of it as a dynamic thing. Marshall said: “Whenever you use the (DNA) template, you will disturb the template, you will change the template. This is not necessarily a bad thing.”
He and his colleagues have already begun to study Other types of DNA changes are related to dysregulation and negative consequences including cancer. They discovered some of the key roles of these changes and the regulation of basic memory-related processes.
Marshall believes that many researchers still find it difficult to regard DNA breaks as the basic regulatory mechanism of gene transcription. “It hasn’t really become popular yet, people still think it’s DNA damage,” but he hopes that his work and the new results of the Tsai team “will open a door for others… for deeper exploration.”</ p>