Authors: Courtney Johnson
A study proposing a novel mechanism of DNA damage repair has recently been carried out by researchers at Lomonosov Moscow State University (Russia). The research indicates that the formation of intranucleosomal DNA loops may play an important role in the detection and repair of damaged DNA ‘hidden’ through its association with histone proteins. The results, which appear in the July issue of Science Advances, could have major implications for our understanding of the development of many diseases caused by mutation accumulation and cell death, including neurodegenerative diseases such as Alzheimer’s.
The study focused in particular on single-strand breaks (SSBs) that have been implicated in a range of neurodegenerative diseases, such as, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. It is estimated that tens of thousands of SSBs occur daily within the cell as a result of oxidative stress and due to the post-mitotic nature of neuronal cells in particular, once cell death occurs they are unable to regenerate, leading to disease development and progression.
Although the repair mechanism for SSB’s, through recognition by PARP-1 or processive enzymes such as Pol-II, is relatively well understood, prior to this recent study it was unknown how SSBs in the non-template (NT) strand of DNA could be detected.
The team, led by Vasily Studitsky (Lomonosov Moscow State University), employed a mononucleosomal in vitro model (developed in 2002) of Escherichia coli RNA polymerase (RNAP), with subsequent recapitulation of results using the yeast polymerase Pol II. They demonstrated that the presence of NT-SSBs in nucleosomal DNA resulted in the arrest of RNAP downstream of NT-SSBs. Data also indicated that this arrest is accompanied by the formation of small intranucleosomal DNA loops, approximately 40–60 bp in size. The authors specify that it is probable that these loops are formed when NT-SSBs are both present and absent, however, when NT-SSBs are present, they stabilize the DNA loops, leading to RNAP arrest by sterically blocking the rotation of the enzyme around the histone octamer. Such limited rotation creates ‘topological locks’ between the DNA, histone proteins and transcribing polymerase.
NT-SSBs affect transcription through nucleosomes but not in histone-free DNA, implying the chromatin-specific nature of this mechanism. In their conclusion, the authors propose that: “The dynamic structure of transcribed chromatin could facilitate DNA repair and render the vast majority of SSBs accessible to the repair machinery.”
Although this DNA reparative mechanism has not yet been demonstrated in vivo, this study paves the way for further research. Due to its implications in the treatment and prevention of various neuropathologies, the proposed mechanism offers possibilities for the development of new strategies to combat neurodegeneration.
Studitsky concluded: “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.”
- Studitsky VM et al. Structure of transcribed chromatin is a sensor of DNA damage. Science Advances doi: 10.1126/sciadv.1500021 (2015) (Epub ahead of print)
- Science Daily press release via eurekalert: sciencedaily.com/releases/2015/07/150703150203.htm
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