‘First-responder’ protein spurs gene to repair DNA

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Mice that lack the so-called “longevity gene” age prematurely and those who have extra copies tend to live longer. But how the gene, known as sirtuin 6 (SIRT6), is activated has been unclear.

One of the molecular functions of SIRT6 is to help repair DNA when the strands of the molecule break. While such disruptions are a result of normal chemical processes that take place in cells, the damage has been linked to aging, as well as several age-related diseases.

Now researchers have discovered a protein that may serve as a first responder, activating SIRT6 and setting in motion a cascade of molecular activity to repair the damaged DNA.

“We wanted to find how SIRT6 receives its signal to spring into action,” says Vera Gorbunova, professor of biology at the University of Rochester. “Once we learn that, we may be able to activate SIRT6 even without stress.”

Worms, flies, and mice share longevity proteins

To find out what activates SIRT6, the researchers alternately applied chemical inhibitors to human skin cells to determine which proteins were essential in getting the gene to repair the broken DNA strands. One protein was involved in activating the gene in response to oxidative stress—c-Jun N-terminal kinase—which goes by the simpler term JNK.

When JNK was inhibited, SIRT6 was not activated and the broken strands of DNA were not repaired efficiently. So in effect, the activated gene serves as a first responder, recruiting DNA repair enzymes to the accident site and putting them to work.

The study, published in Cell Reports, is the latest work by Gorbunova and coauthor Andrei Seluanov, professor of biology, to shed light on the molecular mechanisms that drive the aging process. Their previous work involved understanding the prominence of an inferior DNA repair process later in life, as well as how errant DNA fragments—called jumping genes—are typically kept inactive.

Understanding the molecular, chemical, and genetic process of aging has implications for both longevity and quality of life. While more research and clinical work need to be done, such studies help pave the way for possible treatments in the future.

For example, the results may allow pharmaceutical researchers to one day design drugs that activate SIRT6 in ways that reduce molecular damage, Seluanov says.

“These drugs may be used to protect our genomes from damage, and could ultimately prevent cancer and extend healthy lifespan.”

Source: University of Rochester