Facing a threat, the brain must act quickly, its neurons making new connections to learn what could be the difference between life and death. But in its response, the brain also raises the stakes: as a disturbing recent discovery shows, to express learning and memory genes faster, brain cells break down their DNA at several key points, then rebuild their fractured genome. later.
The discovery doesn’t just provide insight into the nature of brain plasticity. It also demonstrates that DNA disruption can be a common and important part of normal cellular processes, which has implications for how scientists view aging and disease, and how they approach the genomic events they have generally considered bad luck.
The discovery is all the more surprising given that DNA double-strand breaks, in which both rails of the helical ladder are cut at the same position along the genome, are a particularly dangerous type of genetic damage associated with cancer. , neurodegeneration and aging. Double-strand breaks are more difficult for cells to repair than other types of DNA damage, as there is no longer an intact “template” to guide the reattachment of the strands.
Yet it has also long been recognized that DNA breaking sometimes also plays a constructive role. When cells divide, double-stranded breaks allow the normal process of genetic recombination between chromosomes. In the developing immune system, they allow pieces of DNA to recombine and generate a diverse repertoire of antibodies. Double strand breaks have also been implicated in neuronal development and helping activate certain genes. Yet these functions have appeared to be exceptions to the rule that double strand breaks are accidental and unwanted.
Corn a turning point arrived in 2015. Li Huei Tsai, neuroscientist and director of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, and her colleagues were following previous work that had linked Alzheimer’s disease to the buildup of double-stranded breaks in neurons. To their surprise, the researchers found that stimulation of cultured neurons triggered double-stranded breaks in their DNA, and that the breaks rapidly increased the expression of a dozen fast-acting genes associated with synaptic activity in learning and memory.
Double-stranded breaks appeared to be essential in regulating the activity of genes important for the functioning of neurons. Tsai and colleagues hypothesized that the breaks essentially released enzymes that were stuck along twisted pieces of DNA, freeing them to quickly transcribe relevant genes nearby. But the idea “was met with a lot of skepticism,” Tsai said. “People just have a hard time imagining that double-stranded breaks can actually be physiologically important.”
However, Paul marshall, postdoctoral researcher at the University of Queensland in Australia, and his colleagues decided to follow up on this discovery. Their work, which published in 2019, both confirmed and extended the observations of Tsai’s team. He showed that DNA breakdown triggered two waves of improved gene transcription, one immediate and the other several hours later.
Marshall and his colleagues proposed a two-step mechanism to explain the phenomenon: when DNA breaks down, certain enzyme molecules are released for transcription (as Tsai’s group suggested) and the site of the break is also chemically labeled with a methyl group, a so-called epigenetic marker. Later, when repair of the broken DNA begins, the marker is removed, and in the process, even more enzymes can be released, starting the second round of transcription.
“Not only is the double strand break a trigger,” said Marshall, “it then becomes a marker, and that marker itself is functional in terms of regulating and guiding machines to that location.”
Since then, other studies have shown something similar. A, published last year, double-stranded breaks associated not only with the formation of a fear memory, but with its memory.
Now in a study last month in PLOS ONE, Tsai and his colleagues have shown that this counterintuitive mechanism of gene expression may be prevalent in the brain. This time, instead of using cultured neurons, they looked at cells in the brains of living mice that were learning to associate an environment with electric shock. When the team mapped the genes undergoing double-stranded breaks in the prefrontal cortex and hippocampus of shocked mice, they found breaks occurring nearly hundreds of genes, many of which were involved in linked synaptic processes. in memory.