Novel DNA repair mechanism could lead to new Alzheimer's treatments

Their findings are published in the American Association for the Advancement of Science's online-only journal Science Advances.
The DNA damage response - consisting of mechanisms of detection, signaling and repair - is crucial for the health of the body, as unpaired damage to DNA can lead to cell death and the development of severe conditions such as Alzheimer's disease.

In particular, single-strand breaks (SSBs) "can interfere with transcription, replication, and DNA repair; induce accumulation of double-stranded DNA breaks [and] increase genomic instability and apoptosis," the authors write.

DNA is bound alongside proteins in complexes referred to as nucleosomes. In nucleosomes, around 200 base pairs of DNA are wound around a core of histone proteins into two huge coiled loops.

These coils are wound so tightly that molecules the length of around 2 meters can fit into microscopic cell nuclei. Lead researcher Vasily M. Studitsky, a professor at Lomonov Moscow State University in Russia, explains that our entire genome is packed this way.

However, due to the tight coiling, significant surfaces of the DNA are inaccessible - the surfaces interacting with the histones - and, as a result, certain SSBs are unrecognizable by the usual repair enzymes, known as PARP1.

The discovery could herald new forms of drug treatment
The researchers have discovered, however, that a special enzyme - the RNA polymerase II (Pol II) enzyme - can sense these SSBs by "riding" along the DNA coil. Acting almost like a proofreader of a text, when the Pol II enzyme encounters an SSB, it triggers a number of reactions that lead to repair enzymes fixing the damaged area.

"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,'" Prof. Studitsky explains.

For the study, the researchers inserted SSBs into a model DNA system to observe how they would affect the progress of Pol II progressing along the coils. They discovered that this enzyme only stopped upon encountering breaks in the DNA connected to the histones and not in histone-free DNA.

"These observations raise the possibility that nucleosomal structure could affect the process of detection and repair of DNA damages," the authors write.

Prior to the study, the researchers had thought that DNA repair was only possible in histone-free DNA, as reparation with the previously identified mechanism would require complete unwinding of the DNA coils to make the SSBs accessible.

Prof. Studitsky concludes that the discovery of a new method of DNA reparation promises new prospective methods of prevention and treatment of diseases:

"We have shown that the formation of loops, which stop the polymerase, depends on its contacts with histones. If you make them more robust, it will increase the efficiency of the formation of loops and the probability of repair, which in turn will reduce the risk of disease. If these contacts are destabilized, then by using special methods of drug delivery you can program the death of the affected cells."

Recently, Medical News Today reported on a study that discovered how a small molecule known for regulating gene expression plays a key role in progressing wounds through their healing stages.

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