Grant: Operating Grant

Why do we age, how does it promote disease, and can we control aging? Our bodies are built from millions of living entities called cells. Each cell has a copy of our DNA, which is arranged in thousands of units called genes. The cell often needs multiple copies of particular genes to survive. In fact, more than half of human DNA is repetitive. However, repeats create problems. Every time a cell divides, it makes a second copy of its DNA. Major errors can occur as cells copy DNA repeats. For example, repeated genes can get mixed up uncontrollably between the two DNA copies being prepared for cell division. This leads to the gain/loss of DNA creating so many errors that cells eventually fail to copy DNA and divide. But cells have processes that protect repetitive DNA. We previously found that cells stabilize repetitive DNA by anchoring it to internal cellular structures, much like people literally standing on each others' shoulders in a human tower benefit from holding on to a nearby post. In addition, longevity proteins called sirtuins stabilize repeated DNA by compacting it into tight structures. This would be analogous to people sitting on each others' shoulders in the human tower. This research group has new data indicating that a protein present in yeast and humans stabilizes DNA repeats via a new process similar to that of a police officer ensuring that observers of the human tower do not try to sabotage it. This research will reveal how this protein achieves its policing role to protect repeated DNA and maintain yeast/human cellular lifespan. Mutations in this protein are linked to the neurological diseases ataxia and also ALS. These diseases disrupt the brain, body movement control, and eventually life. This research will test contributions of DNA repeat instability to disease and point to therapeutic avenues. All in all, this project may allow us to counteract cellular aging and prevent/cure its related diseases.