Biology – A Tufts University study sheds new light on the process by which DNA repair occurs within the cell.
In research published in the May 15 edition of the journal Genes & Development and available May 4 online in advance of print, Tufts University biologist Catherine Freudenreich and her co-authors show that expanded repeats of the CAG/CTG trinucleotide (CAG) in yeast shift to the periphery of the cell nucleus for repair.
This shift is important for preventing repeat instability and genetic disease.
CAG expansions are significant because they are at the root of several neurodegenerative and neuromuscular diseases such as Huntington’s disease, myotonic dystrophy and multiple subtypes of spinal cerebella ataxia.
Short triplet repeats do not always cause problems. However, sometimes short triplet repeats expand and become longer than normal. The expanded repeat sequences change the shape of the DNA molecule from a double helix into a hairpin-like structure that is difficult for the cellular machinery to replicate and repair and can cause breakage of the DNA molecule.
Normally, each single strand of DNA serves as a template for remaking the other strand. The enzymes involved in DNA replication rebuild each strand to make two chromosomes out of one. One section of the double-stranded DNA molecule is separated into two single strands. The resulting Y-shaped structure is called the replication fork. This process stalls when there is a problem with the DNA.
At the periphery, the damaged DNA interacts with the nuclear pore complexes (NPCs), a complex of proteins that serves as gatekeeper between the cell’s nucleus and the surrounding cytoplasm. One of these gatekeepers is the Nup84 complex and the associated Slx5/8 complex. They are present at every NPC.
The research team showed that both of these complexes are needed for repeat DNA to be repaired properly. The Slx5/8 complex plays a vital role: it is required for tethering the repeat DNA to the NPC, and it appears to regulate a known repair protein (Rad52) in order to facilitate appropriate repair, thereby preventing repeat expansions and chromosome breakage.