The brain must react quickly to a threat. Its neurons make new connections to discover what could mean the difference between life or death. The brain's response raises the stakes. Recent research shows that brain cells can snap their DNA at key points to express memory and learning genes faster. They then reconstruct their fragmented genome later.
This discovery provides insight into brain plasticity, but more. This finding also shows that DNA breaking may be an important and routine part of normal cell processes. This has implications for scientists' thinking about aging, disease, and how to approach genomic events they have previously dismissed as bad luck.
This discovery is even more shocking because DNA double-strand break, which occurs when both rails on the helical ladder are cut at the same place along the genome, is a very dangerous form of genetic damage that can lead to cancer, neurodegeneration, and aging. Double-strand break repair is more difficult than other types of DNA damage, as there is no template to guide the reattachment.
It has been long recognized that DNA breaks can play a positive role. Double-strand breaks are necessary for normal genetic recombination among chromosomes. They allow DNA fragments to recombine, generating a variety of antibodies in the developing immune system. Double-strand breaks are also implicated in neuronal growth and helping to turn on certain genes. These functions are considered exceptions to the rule that double strand breaks are unwelcome and accidental.
2015 was a pivotal year. Li-Huei Tsai (a neuroscientist and director of Picower Institute for Learning and Memory, Massachusetts Institute of Technology) and her colleagues were reexamining previous research that suggested Alzheimer's disease was linked to double-strand breaks in neurons. The researchers were surprised to discover that stimulating cultured neurons caused double-strand breaks in DNA. These breaks also increased expression of a dozen genes involved in synaptic activity, such as memory and learning.
Double-strand breaks were essential in regulating genes that are important for neurons function. Tsai and her colleagues hypothesized that enzymes stuck to DNA twisted by the breaks would release them, allowing them to quickly transcribe nearby genes. Tsai stated that the idea was met with much skepticism. It is difficult to imagine that double-strand breaks could be vital for physiological reasons.
Paul Marshall, a postdoctoral researcher from the University of Queensland, Australia, decided to investigate the finding with his colleagues. Their research, published in 2019, confirmed and expanded the findings of Tsais's team. It revealed that DNA breaking caused two waves of enhanced gene transcription, one immediately and one several hours later.
Marshall and his coworkers proposed a two-step explanation for the phenomenon. When DNA breaks, enzyme molecules are released for transcription (as the Tsais group suggested). The epigenetic marker chemically marks the location of the break with a methyl groups. The marker is then removed when the repair of the DNA starts. During this process, more enzymes may spill out, initiating the second round.
Marshall stated that the double-strand break is not only a trigger but also a marker. That marker is functional in terms regulating and guiding machinery towards that location.
Other studies have since confirmed the same results. A study published last year found that double-strand breaks are associated with fear memories and their recollection.
Tsai and her collaborators have now shown that the brain might possess this counterintuitive mechanism for gene expression in a study published in PLOS ONE last month. Instead of studying cultured neurons, the team looked at living cells that learned to associate electric shocks with environments. The team discovered that double-strand breaks occurred in the prefrontal cortex, hippocampus, and hippocampus, which was where the mice had been shocked. Many of these breaks were related to synaptic processes, such as memory.
It was also interesting to note that double-strand breaks occurred in neurons of mice who had not been shocked. These breaks occur just as normal in the brain, according to Timothy Jarome, a neuroscientist from Virginia Polytechnic Institute and State University, who was not involved in the study, but has done similar work. This is the most remarkable aspect of this study, as it suggests that it happens all the time.
The scientists also found double-strand breaks in nonneuronal brain cells called Glia. They regulate a different set of genes, further supporting this conclusion. This suggests that glia play a role in the storage and formation of memories. It also suggests that DNA breaks might be an important regulatory mechanism in other cell types. Jarome stated that it's likely a more complex mechanism than we believe.
It is possible to break DNA, but it can also be risky. This could happen for memory consolidation, or other cellular functions. Genetic information could be lost if double-strand breaks happen at the same places over and over again, and aren't properly repaired. Tsai stated that this type of gene regulation could make neurons more vulnerable to genetic lesions, particularly as they age and are exposed to neurotoxic conditions.
It's interesting that it is used so extensively in the brain, according to Bruce Yankner, who is a Harvard Medical School neurologist/geneticist and was not involved with the new work. The cells can also get away without causing any damage that could be catastrophic.
This is likely because the repair process works well and is effective, but this could change as we age. Marshall, Tsai and other researchers are investigating whether or not this could be a mechanism for neurodegeneration in conditions like Alzheimer's disease. Yankner believes it could be a contributing factor to glial cancers and post-traumatic stress disorder. Double-strand breaks can also affect gene activity outside of the nervous system. This could lead to muscle loss and heart disease.
They could help guide the development and implementation of new medical treatments as the details and uses of the mechanism in the body improve. Marshall stated that preventing double-strand breaks is not the best approach. They are essential in basic memory processes.
The work also shows that we need to think about the genome as dynamic and not static. Marshall stated that if you use the [DNA] template, it is unstable and you can change the template. This is not always a bad thing.
His colleagues and he have begun to study other DNA modifications that can lead to dysregulation and potentially harmful consequences, such as cancer. These changes play a critical role in the regulation of basic memory-related processes.
Marshall believes many researchers are still having difficulty understanding the role of DNA breaking in gene transcription. He said that it hasn't caught on yet. It is still a controversial idea that DNA damage can occur, but people are still open to it. He hopes his work and those of the Tsais team will allow others to investigate further.
