Summary: A new study shows that the DNA repair enzyme Polβ plays a critical role in protecting the developing brain from harmful mutations. The researchers found that without Polβ, insertion-deletion mutations near CpG sites increase dramatically, compromising genetic stability during critical stages of brain development.
These regions are essential for the regulation of gene activity and are particularly vulnerable to DNA demethylation. These findings shed light on the molecular causes of neurodevelopmental disorders and suggest new approaches for their prevention and treatment.
Key data
- Polβ function: Repairs DNA damage during brain development, preventing harmful indel mutations.
- Mutation increase: Loss of Polβ results in a ninefold increase in indel mutations at CpG sites.
- Health effects: The findings link DNA repair deficiencies to neurodevelopmental disorders and have implications for cancer and aging research.
Source: Osaka University
A research group led by Osaka University has discovered that the DNA repair enzyme Polβ plays a critical role in protecting the developing brain from harmful mutations.
Research has shown that Polβ deficiency leads to a significant increase in small DNA insertions and deletions near CpG sites, which are key regulatory regions of genes. This accumulation of mutations may contribute to neurodevelopmental disorders.
The human brain undergoes a complex developmental process, carefully controlled by its genetic makeup. However, during these stages, DNA damage can occur. If not properly repaired, this can potentially lead to irreversible mutations in nerve cells. Although the presence of these mutations is known, the precise mechanisms by which they are suppressed remain unknown.
The study shows that Polβ is essential for preventing a specific type of mutation, called an insertion-deletion (indel), near CpG sites, regions of the genome where there is high gene regulatory activity. During brain development, these sites undergo dynamic changes in methylation, a chemical modification of DNA. The researchers discovered that Polβ repairs DNA damage associated with demethylation at these sites, thereby preventing the accumulation of indel mutations. In the absence of Polβ, indel mutations near CpG sites increased by about ninefold.
The study uncovers a novel function of Polβ, showing that it plays a vital role in preserving the genetic stability of brain cells as they develop. By safeguarding DNA integrity during these critical stages, Polβ helps ensure proper neuronal formation and healthy brain function. By acting as a key player in DNA repair processes, Polβ ensures that the delicate genetic code within developing neurons remains intact, preventing harmful mutations that could disrupt normal brain formation and function.
This breakthrough expands our knowledge of the brain’s built‑in mechanisms for protecting its genetic material, offering fresh insight into the molecular origins of neurological and psychiatric disorders.
By focusing on Polβ-related pathways, scientists may eventually develop innovative treatments aimed at safeguarding brain health from the very earliest stages of development, potentially preventing or mitigating disease before it begins. The results suggest that Polβ deficiency may contribute to neurodevelopmental disorders as a result of mutation accumulation. This research provides a new molecular basis for understanding the pathogenesis of brain developmental disorders and may contribute to future prevention techniques.
Lead author Dr. Noriyuki Sugo highlighted that this research is the first to demonstrate the vital role of Polβ in protecting developing nerve cells from harmful mutations. By showing how this enzyme actively safeguards the genetic material during brain development, the study provides compelling evidence of its importance in maintaining the integrity of the nervous system at its earliest stages.
This breakthrough uncovers a previously unknown mechanism that preserves the genome’s stability, a process essential for healthy brain formation and function. The findings not only deepen our understanding of neuronal development but also open new possibilities for investigating how defects in DNA repair pathways may contribute to neurological and psychiatric disorders.
By revealing how Polβ functions during the formation of nerve cells, the study opens new avenues for understanding neurological disorders linked to DNA damage. The findings could pave the way for future research into targeted therapies aimed at protecting genome integrity in the nervous system.
We believe this discovery opens up a new perspective on the causes of neurodevelopmental disorders and opens up new avenues for research in neuroscience, cancer, and aging. The team plans to further investigate the link between Polβ dysfunction and certain neurodevelopmental disorders.
Abstract
DNA polymerase β plays a crucial role in safeguarding developing cortical neurons by repairing and removing somatic insertion–deletion mutations (indels) that occur at CpG dinucleotides—genomic regions important for regulating gene activity.
Such somatic mutations in cortical neurons have been linked to various psychiatric disorders, suggesting that defects in this repair process could contribute to the molecular origins of these conditions.
Although endogenous DNA damage and repair errors during development may contribute to these mutations, the underlying mutagenic mechanism remains unclear.
In this study, we investigated somatic mutations in immature cortical neurons using embryonic stem cells derived from mouse somatic cell nuclear transfer and genome sequencing. Insertions and deletions (indels) were frequently observed in both repetitive and non-repetitive sequences of wild-type cells.
The absence of DNA polymerase β (Polβ)—a key enzyme responsible for gap filling during base excision repair and for TET-mediated DNA demethylation—was shown to severely compromise genome stability in developing brain cells.
In neural progenitor cells, loss of Polβ caused approximately a fivefold rise in insertion–deletion mutations (indels) at cytosine-phosphate-guanine (CpG) sites, which are vital for controlling gene expression.
This surge in mutation frequency suggests that Polβ plays a vital protective role in maintaining DNA integrity during brain development. Disruption of this repair mechanism could have significant consequences for neuronal function and may contribute to the molecular origins of neurodevelopmental and psychiatric disorders.
These mutations were enriched in neuronal genes, resulting in frameshift mutations, amino acid insertions/deletions, and gain and loss of CpG sites in regulatory regions.
Our results suggest that Polβ preferentially repairs DNA damage at CpG sites by TET-mediated active demethylation, thereby suppressing mutagenesis associated with neuronal gene activation during cortical development.
