Face one Threatening, the brain must act quickly, and its neurons establish new connections to understand what might mean the difference between life and death. But in its response, the brain also increases the risk: as a recent disturbing discovery has shown, in order to express learning and memory genes faster, brain cells break down their DNA into fragments at many key points and then rebuild it. Their broken genomes.
This discovery not only provides insights into the nature of brain plasticity. It also suggests that DNA fragmentation 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 that they usually consider to be just bad luck.
This finding is even more surprising because DNA double-strand breaks (in which the two tracks of the spiral ladder are cut at the same position in the genome) are a particularly dangerous genetic damage associated with cancer, neurodegeneration, and aging. Compared with other types of DNA damage, it is more difficult for cells to repair double-strand breaks because there is no complete “template” to guide the reconnection of the double-strands.
However, it has long been recognized that DNA breaks can sometimes play a constructive role. When a cell divides, a double-strand break allows the normal process of gene recombination between chromosomes. In the developing immune system, they enable DNA fragments to recombine and produce multiple antibodies.Double-strand breaks are also implicated In neuron development And helping Turn on certain genesNonetheless, these functions seem to be exceptions to the rule that double-strand breaks are accidental and unwelcome.
but Turning point Appeared in 2015. Cai LihuiThe neuroscientist and director of the Picall Institute for Learning and Memory at MIT, and her colleagues are following up on previous work that links Alzheimer’s disease to the accumulation of double-strand breaks in neurons. To their surprise, the researchers found that stimulating cultured neurons triggered double-strand breaks in their DNA, and the breaks rapidly increased the expression of a dozen fast-acting genes related to synaptic activity in learning and memory.
Double-strand breaks seem to be essential for regulating the activity of genes that are important for neuronal function. Tsai and her collaborators hypothesized that the break basically releases enzymes stuck along the twisted DNA segment, allowing them to quickly transcribe nearby related genes. But this idea “was met with a lot of skepticism,” Cai said. “It’s hard to imagine that double-strand breaks are actually physiologically important.”
despite this, Paul MarshallA postdoctoral researcher at the University of Queensland in Australia and his colleagues decided to follow up on this discovery. their job, Appeared in 2019, Both confirmed and expanded the observation results of the Chua team. The results showed that the DNA break triggered two waves of enhanced gene transcription, one wave immediately and the other 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 (as suggested by Tsai’s group), and the break site is chemically labeled It is a methyl group, so it is called an epigenetic marker. Later, when the broken DNA starts to be repaired, the marker is removed—in the process, more enzymes can freely overflow and start the second round of transcription.
“It’s not only the double-strand break that is the trigger,” Marshall said, “it then becomes a mark, and the mark itself plays a role in regulating and guiding the machine to that location.”
Since then, other studies have proved a similar situation. one, Published last year, The related double-strand break is not only related to the formation of fear memory, but also related to its memory.
Now in a Studied last month exist Public Library One, Cai and her colleagues have shown 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 genes that have double-strand breaks in the prefrontal cortex and hippocampus of mice that received electric shocks, they found that breaks occurred near hundreds of genes, many of which were related to synaptic processes related to memory.