Facing a threat, the brain must act quickly, its neurons create new connections to learn what the difference between life and death can mean. But in response, the brain also raises stakes: As a disturbing recent discovery shows, in order to more quickly express genes for learning and memory, brain cells break their DNA into pieces at many key points and then repair their broken genome later.
The discovery not only gives an idea of the nature of the plasticity of the brain. He also demonstrated that DNA breakage can be a routine and important part of normal cellular processes – which has an impact on the way scientists think about aging and disease and how they approach genomic events that they usually write off as just bad luck. .
The discovery is even more surprising because double-stranded DNA breaks, in which both spiral stair rails are cut in the same place along the genome, are a particularly dangerous type of genetic damage associated with cancer, neurodegeneration and aging. It is more difficult for cells to repair double-stranded fractures than other types of DNA damage because there is no “pattern” left intact to guide the reattachment of the strands.
Yet it has long been recognized that DNA breakage sometimes 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-stranded interruptions are also involved in the development of neurons and in promoting the incorporation of certain genes. Yet these features seemed to be exceptions to the rule that double-chain interruptions were random and undesirable.
But a turning point came in 2015. Li-Huei Tsai, a neurologist and director of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, and her colleagues traced previous work linking Alzheimer’s disease to the accumulation of double-stranded breaks in neurons. To their surprise, the researchers found that stimulation of cultured neurons caused double-stranded breaks in their DNA, and the breaks quickly increased the expression of a dozen fast-acting genes associated with synaptic activity in learning and memory.
The two-strand breaks seemed essential to regulate gene activity important for neuronal function. Tsai and her co-workers suggested that breaks essentially release enzymes that are glued to twisted pieces of DNA, freeing them to rapidly transcribe relevant related genes. But the idea was “met with a lot of skepticism,” Tsai said. “People just have a hard time imagining that double-strand breaks can actually be physiologically important.”
Nevertheless, Paul Marshall, a doctoral student at the University of Queensland in Australia, and his colleagues decided to follow up. Their work, which appeared in 2019, confirmed and expanded the observations of Tsai’s team. He showed that the DNA breakage touched two waves with improved gene transcription, one immediately and one a few hours later.
Marshall and colleagues proposed a two-step mechanism to explain the phenomenon: When DNA breaks down, some enzyme molecules are released for transcription (as suggested by the Tsai group), and the fracture site is also chemically labeled with a methyl group, called an epigenetic marker. Later, when the repair of the broken DNA begins, the marker is removed – and in the process, even more enzymes can spill out, starting with the second round of transcription.
“Not only is double breakage included as a trigger,” Marshall said, “then it becomes a marker and the marker itself is functional in terms of adjusting and directing the machines to that location.”
Since then, other studies have shown something similar. One, published last year, links double-chain breaks not only to the formation of a memory of fear, but also to its recollection.
Now, in a survey last month in PLOS ONE, Tsai and her 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 live mice that were learning to connect the environment to an electric shock. When the team mapped genes subjected to double-strand breaks in the frontal cortex and hippocampus of mice that were shocked, they found breaks occurring near hundreds of genes, many of which were involved in synaptic processes related to memory.