Role of DNA Repair Enzyme Polβ in Protecting the Developing Brain from Mutations

A groundbreaking study led by researchers from the University of Osaka has highlighted the critical role of the DNA repair enzyme DNA polymerase β (Polβ) in safeguarding the developing brain from harmful genetic mutations. During brain development, DNA undergoes various modifications, including demethylation at enhancer regions, which is essential for proper gene activation. However, these processes can introduce DNA damage, leading to insertion and deletion mutations, known as indels, particularly near CpG sites that are crucial for gene regulation.

The research demonstrates that Polβ is vital in repairing DNA damage associated with demethylation events. Without sufficient Polβ activity, there is a notable ninefold increase in indel mutations near CpG dinucleotides, which could disrupt normal neural development. This discovery underscores a previously unrecognized function of Polβ in maintaining genome stability during neurodevelopment.

These findings are significant because the accumulation of mutations in neural tissues may contribute to neurodevelopmental disorders. Understanding the molecular mechanisms behind these mutations offers promising avenues for future research into neurological conditions and potential preventative strategies. Dr. Noriyuki Sugo, the lead author, emphasized that this study is the first to demonstrate Polβ’s essential role in preventing mutations during cortical neuron development, opening new paths to explore in neuroscience, cancer, and aging studies.

The research was published in the Proceedings of the National Academy of Sciences, providing new insights into how DNA repair processes influence brain development and the potential consequences of deficiencies in these mechanisms.