DNA Damage as a Necessary Mechanism

Researchers here present the intriguing possibility that the same very same nuclear DNA damage that may be a contribution to degenerative aging is also an essential part of cellular operation in some vital tissues and processes:

Each time we learn something new, our brain cells break their DNA, creating damage that the neurons must immediately repair. This process is essential to learning and memory. "Cells physiologically break their DNA to allow certain important genes to be expressed. In the case of neurons, they need to break their DNA to enable the expression of early response genes, which ultimately pave the way for the transcriptional program that supports learning and memory, and many other behaviors." However, as we age, our cells' ability to repair this DNA damage weakens, leading to degeneration. "When we are young, our brains create DNA breaks as we learn new things, but our cells are absolutely on top of this and can quickly repair the damage to maintain the functionality of the system. But during aging, and particularly with some genetic conditions, the efficiency of the DNA repair system is compromised, leading to the accumulation of damage, and in our view this could be very detrimental."

In previous research into Alzheimer's disease in mice, the researchers found that even in the presymptomatic phase of the disorder, neurons in the hippocampal region of the brain contain a large number of DNA lesions, known as double strand breaks. They discovered that of the 700 genes that showed changes as a result of this damage, the vast majority had reduced expression levels, as expected. Surprisingly though, 12 genes - known to be those that respond rapidly to neuronal stimulation, such as a new sensory experience - showed increased expression levels following the double strand breaks. To determine whether these breaks occur naturally during neuronal stimulation, the researchers then treated the neurons with a substance that causes synapses to strengthen in a similar way to exposure 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."

Finally, the researchers attempted to determine why the genes need such a drastic mechanism to allow them to be expressed. Using computational analysis, they studied the DNA sequences near these genes and discovered that they were enriched with a motif, or sequence pattern, for binding to a protein called CTCF. This "architectural" protein is known to create loops or bends in DNA. In the early-response genes, the bends created by this protein act as a barrier that prevents different elements of DNA from interacting with each other - a crucial step in the genes' expression. The double strand breaks created by the cells allow them to collapse this barrier, and enable the early response genes to be expressed. "Surprisingly then, even though conventional wisdom dictates that DNA lesions are very bad - as this 'damage' can be mutagenic and sometimes lead to cancer - it turns out that these breaks are part of the physiological function of the cell."

Link: http://newsoffice.mit.edu/2015/dna-breakage-learning-age-related-damage-0604

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