Given the fundamental importance of our DNA, it is logical to assume that damage to it is undesirable and spells bad news; after all, we know that cancer can be caused by mutations that arise from such injury. But a surprising new study is turning that idea on its head, with the discovery that brain cells actually break their own DNA to enable us to learn and form memories.

While that may sound counterintuitive, it turns out that the damage is necessary to allow the expression of a set of genes, called early-response genes, which regulate various processes that are critical in the creation of long-lasting memories. These lesions are rectified pronto by repair systems, but interestingly, it seems that this ability deteriorates during aging, leading to a buildup of damage that could ultimately result in the degeneration of our brain cells.

This idea is supported by earlier work conducted by the same group, headed by Li-Huei Tsai, at the Massachusetts Institute of Technology (MIT) that discovered that the brains of mice engineered to develop a model of Alzheimer’s disease possessed a significant amount of DNA breaks, even before symptoms appeared. These lesions, which affected both strands of DNA, were observed in a region critical to learning and memory: the hippocampus.

To find out more about the possible consequences of such damage, the team grew neurons in a dish and exposed them to an agent that causes these so-called double strand breaks (DSBs), and then they monitored the gene expression levels. As described in Cell, they found that while the vast majority of genes that were affected by these breaks showed decreased expression, a small subset actually displayed increased expression levels. Importantly, these genes were involved in the regulation of neuronal activity, and included the early-response genes.

Since the early-response genes are known to be rapidly expressed following neuronal activity, the team was keen to find out whether normal neuronal stimulation could also be inducing DNA breaks. The scientists therefore applied a substance to the cells that is known to strengthen the tiny gap between neurons across which information flows – the synapse – mimicking what happens when an organism is exposed to a new experience.  

“Sure enough, we found that the treatment very rapidly increased the expression of those early response genes, but it also caused DNA double strand breaks,” Tsai said in a statement.

So what is the connection between these breaks and the apparent boost in early-response gene expression? After using computers to scrutinize the DNA sequences neighboring these genes, the researchers found that they were enriched with a pattern targeted by an architectural protein that, upon binding, distorts the DNA strands by introducing kinks. By preventing crucial interactions between distant DNA regions, these bends therefore act as a barrier to gene expression. The breaks, however, resolve these constraints, allowing expression to ensue.

These findings could have important implications because earlier work has demonstrated that aging is associated with a decline in the expression of genes involved in the processes of learning and memory formation. It therefore seems likely that the DNA repair system deteriorates with age, but at this stage it is unclear how these changes occur, so the researchers plan to design further studies to find out more.