To Learn More Quickly, Brain Cells Break Their DNA

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 finding 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' understanding of aging and disease and how to approach genomic events they have previously dismissed as bad luck.

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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 DNA repair begins. During this process, more enzymes may spill out, thereby starting 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.