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DNA Repair Under Stress

DNA repair mechanisms are a re-occurring topic here at Evolution, News, and Views because scientists are constantly uncovering layers of complexity and integration within the DNA repair system that seem to defy any notions of having developed by a random, step-by-step process. DNA repair systems behave as if a command center has notified the cell of damage to DNA, and then the cell dispatches the appropriate units for the particular job at a particular location. So not only is the "double strand" team or the "nucleotide replacement" team dispatched when needed, but the team that would be the most efficient job for the particular cause of damage is dispatched. Another way to think of it is a basketball coach who knows exactly what player to put in not only for a particular play, but against a particular opponent. Here we report on a brief article in Science that discusses an enzyme that is recruited at a different point during DNA repair based on the conditions of the DNA strand. To go back to the basketball analogy, sometimes this enzyme is a starter and sometimes it is a bench player.

Sirtuin proteins are a class of proteins that have been in the news in the last few years for their possible role in affecting the aging process. One type of sirtuin protein gained attention for its role in mice that were put on a low calorie diet. Mammalian sirtuin proteins (SIRT1 - SIRT6) are also known to respond in DNA repair and to DNA stress. DNA is "stressed" when there are certain conditions, usually from a cellular process, that produce chemicals that could damage DNA. For example, oxidative stress is one of the most harmful for DNA. A cellular process might produce a chemical species that is highly reactive (such as a hydroxyl radical) and will react with the first thing it sees, including DNA. In severe cases, oxidative stress can cause cell death. Studies have also shown that cells that are deficient in sirtuin proteins cannot repair double strand breaks (DSBs) as effectively as those that have appropriate sirtuin levels.

The authors of the Science paper wanted to see if certain sirtuin proteins "may promote longevity by integrating stress signaling and DNA DSBs repair pathways."

What they found was that SIRT6, a protein that has been shown to be involved in DNA double strand repair, seems to have a more interesting function than just being part of the double strand dispatch team. SIRT6 plays a small role in double strand repair under normal conditions; however, under oxidative stress conditions, SIRT6 plays a much more important role.

Under normal conditions, a team of enzymes repairs a DSB. SIRT6 is one of the enzymes that is recruited much later in the process, and plays a smaller role in repair. One of the studies in this article showed that after gamma-irradiation, which causes a DSB, SIRT6 was recruited after 8-to-10 hours. However, keeping all other conditions the same except for pre-treating the DNA with paraquat, a chemical that causes oxidative stress, SIRT6 was recruited about thirty minutes after irradiation.

The authors carried out several experiments to test the efficiency of DSB repair when SIRT 1, SIRT2, SIRT6, and SIRT7 are over-expressed. They found that under various types of oxidative stress, SIRT6 (and to some degree SIRT7) stimulated DSB repair, but under normal conditions, these enzymes did not play as big of a role in stimulating DSB repair. Inhibiting SIRT6 in the stressed DNA also caused a drop in efficiency of DSB repair, meaning that SIRT6 plays an important role in DSB repair when DNA is stressed.

The authors conclude:

In the absence of oxidative stress, SIRT6 overexpression mildly induced repair, whereas under stress DNA repair was stimulated 16-fold. This observation suggests that SIRT6 plays a regulatory function in DNA repair by integrating DNA repair and stress signaling pathways.

This study shows a DNA repair mechanism that has been programmed to recruit SIRT6 in a different way based on the particular conditions of the DNA. This level of organization and specificity makes SIRT6 look like the right tool designed for the right job.