In normal individuals there are short repetitive sequences, for example, CAGCAGCAG at these genomic locations. In patients, however, these sequences have expanded (increased in length) sometimes reaching hundreds or even thousands of repetitive units. This causes serious problems and patients progressively lose neurons. We do not understand how short sequences can expand to cause the disease.
The goal of this proposal is to understand how the repetitive sequences change in length.
We know that the expanded repeats fool the cell into thinking that it is damaged DNA, which triggers DNA repair proteins to act on these sequences when they should not. Because these sequences are repetitive in nature, they are not repaired properly, leading to changes in the length of the repeat tract. If we could better understand the genetic factors and the way they process the repeat tract, we could perhaps design a therapeutic approach aimed at shrinking the size of the repeat tract down to the size found in normal individuals. In this proposal, we aim to identify new factors involved in changing the size of the repeat tracts. Specifically, we will look for factors involved in changing the way DNA is packaged into the nucleus of a cell.
Each human cell has about 2 meters worth of DNA tightly packaged into a nucleus that is much smaller than the diameter of a hair. The amalgam of DNA and proteins that allow this compaction is called chromatin. Chromatin is important for DNA repair in ways we do not completely understand. Here we aim to test the idea that the packaging of expanded repeats is involved in their inappropriate repair and therefore in changing the repeat length. In the future, we hope to use this information to design novel therapeutic approaches for these neurological diseases.