Neuronal DNA Damage ‘Hot Spots’ Provide New Angle on Neurodegeneration and Its Treatment

Illustration of a damaged ribonucleic acid or  dna strand
[Source: Christoph Burgstedt/Getty Images]

Researchers at the National Institutes of Health (NIH) have shown that specific regions within the DNA of neurons accumulate high rates of single-strand breaks (SSBs). This process appears to be unique to neurons and challenges what is generally understood about the cause of DNA damage and its potential implications in neurodegenerative diseases.

The researchers say that their work, which was done using synthesis-associated with repair sequencing (SAR-seq), suggests the DNA damage in neurons can actually be part of normal gene regulation.

Defects in DNA repair can lead to neurodevelopmental and neurodegenerative disease, which are widespread problems with few treatments. It is estimated that 5 million Americans suffer from Alzheimer’s disease alone. Because neurodegenerative diseases strike primarily in mid- to late-life, the incidence is expected to soar as the population ages: 30 years from now, more than 12 million Americans could have such conditions.

Because neurons require considerable amounts of oxygen to function properly, they are exposed to high levels of free radicals, which can damage DNA. Normally, this damage occurs randomly. However, in this study, damage within neurons was often found within enhancers, which control the activity of nearby genes.

The senior authors of the Nature paper describing this research are Michael E. Ward, MD, PhD, at the National Institute of Neurological Disorders and Stroke (NINDS) and Andre Nussenzweig, PhD, at the National Cancer Institute (NCI).

To map area of DNA damage, Nussenzweig and colleagues added a thymidine analog, called EdU, to non-dividing neurons to track DNA synthesis during DNA repair. They found that DNA repair occurred specifically at enhancers. The researchers write: “Genome-wide mapping reveals that SSBs are located within enhancers at or near CpG dinucleotides and sites of DNA demethylation.  These SSBs are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair increase DNA repair synthesis at neuronal enhancers, whereas defects in long-patch repair reduce synthesis.”

A significant number of SSBs occurred when methyl groups were removed, which typically makes that gene available to be expressed. The researchers suggest that the removal of the methyl group from DNA itself creates a SSB, and neurons have multiple repair mechanisms at the ready to repair that damage as soon as it occurs. This challenges the common wisdom that DNA damage is inherently a process to be prevented. Instead, at least in neurons, it may be part of the normal process of gene regulation. Furthermore, this work implies that defects in the repair process, not the DNA damage itself, can potentially lead to developmental or neurodegenerative diseases.

This study involved the collaboration between two labs at the NIH: one run by Ward and the other by Nussenzweig, who developed the method for mapping DNA errors within the genome. This highly sensitive technique requires a considerable number of cells in order to work effectively, and Ward’s lab provided the expertise in generating a large population of neurons using induced pluripotent stem cells (iPSCs) derived from one human donor. Keith Caldecott, PhD, at the University of Sussex also provided his expertise in single strand break repair pathways.

The two labs are now looking more closely at the repair mechanisms involved in reversing neuronal SSBs and the potential connection to neuronal dysfunction and degeneration.

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