New DNA Repair Mechanism Opens Doors For Treating Neurodegenerative Diseases

A novel way of repairing damaged DNA has been found by researchers at Lomonosov Moscow State University, opening new doors for potential treatment and prevention of neurodegenerative diseases.

Vasily M. Studitsky, head of the Laboratory of Regulation of Transcription and Replication at the Biological Faculty of the Lomonosov Moscow State University, explained:

“In higher organisms DNA is bound with proteins in complexes called the nucleosome. Every ~200 base pairs are organized in nucleosomes, consisting of eight histone proteins, which, like the thread on the bobbin, wound double helix of DNA, which is coiled into two supercoiled loops. Part of the surface of the DNA helix is hidden, because it interacts with histones. Our entire genome is packed this way, except for the areas, from which the information is being currently read.”

A DNA molecule with a length of about two meters can fit into a microscopic cell nucleus, thanks to this dense packing, but it makes significant surfaces of the DNA inaccessible for repair enzymes, the proteins that manage the “repair” of damaged DNA regions.

Damage to DNA, if not repaired, leads to accumulations of mutations, cell death, and to the development of various diseases, including neurodegenerative, for example, Alzheimer’s.

DNA Repair

During the transcription of genetic information, RNA polymerase enzymes “rides” along on the DNA chain, and stops when it finds the break. The RNA polymerase triggers a series of reactions, resulting in the repair enzymes fixing the damaged area. At the same time, the RNA polymerase cannot detect discontinuities present in the other DNA strand.

“We have shown, not yet in the cell, but in vitro, that the repair of breaks in the other DNA chain, which is “hidden” in the nucleosome, is still possible. According to our hypothesis, it occurs due to the formation of special small DNA loops in the nucleosome, although normally DNA wounds around the histone “spool” very tightly,” says Vasily M. Studitsky.

“The loops form when the DNA is coiled back on nucleosome together with polymerase. RNA polymerase can “crawl” along the DNA loops nearly as well as on histone-free DNA regions, but when it stops near locations of the DNA breaks, it “panics,” triggering the cascade of reactions to start DNA “repairs.”

In the experiment, special sites where single-stranded breaks can be introduced by adding specific enzymes in a test tube, were inserted into the DNA.

Next, a single nucleosome transcribed by a single RNA molecule was studied. In this model system, which was developed in 2002 by the same group of scientists, histones were assembled on the molecule with an accuracy within one nucleotide.

Having introduced breaks at precise locations on the DNA, the researchers looked at the impact of breaks on the progression of the RNA polymerase.

It turned out that only in nucleosomes, rather than in the histone-free DNA, did the enzyme stop when the break was present in the other DNA strand. It did not stop before the break, but immediately after it.

An analysis of breaks in numerous positions allowed the researchers to hypothesize that the stalling of RNA polymerase is due to the formation of the loop, which blocks movement of the enzyme. The findings suggest a new direction for DNA repair research.

Vasily M. Studitsky et al
Structure of transcribed chromatin is a sensor of DNA damage
Science Advances, July 2015 DOI: 10.1126/sciadv.1500021