Loss of Polβ leads to increased mutations in developing neurons, potentially contributing to neurodevelopmental disorders.

Osaka, Japan - A research group led by The University of Osaka has discovered that the DNA repair enzyme Polβ plays a crucial role in protecting the developing brain from harmful mutations. The study found that a lack of Polβ leads to a significant increase in small insertions and deletions of DNA, known as indels near CpG sites, which are important regulatory regions in genes. This accumulation of mutations could contribute to neurodevelopmental disorders.

The human brain undergoes intricate developmental processes, meticulously guided by genetic blueprints. However, DNA damage can occur during these stages, potentially leading to irreversible mutations in nerve cells if not properly repaired. While the occurrence of such mutations has been recognized, the precise mechanisms governing their suppression remained elusive.

This study demonstrates that Polβ is essential in preventing a specific type of mutation known as insertion-deletion (indel) mutations near CpG sites, regions of the genome with high gene regulatory activity. These sites undergo dynamic changes in methylation, a chemical modification of DNA, during brain development. The researchers found that Polβ repairs the DNA damage associated with demethylation at these sites, preventing the accumulation of indel mutations. In the absence of Polβ, indel mutations near CpG sites increased approximately ninefold.

This research highlights a previously unknown role of Polβ in safeguarding the integrity of the genome during brain development. The findings suggest that deficiencies in Polβ could contribute to neurodevelopmental disorders arising from accumulated mutations. This research provides a new molecular basis for understanding the origin of brain developmental disorders and may contribute to preventative techniques in the future.

“Our study is the first in the world to demonstrate the crucial role of Polβ in preventing mutations in developing nerve cells,” says Dr. Noriyuki Sugo, the lead author of the study. “We believe this finding offers a new perspective on the causes of neurodevelopmental disorders and opens up exciting avenues for neuroscience, cancer, and aging research.” The team plans to further investigate the link between Polβ dysfunction and specific neurodevelopmental conditions.

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The article, “DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons,” was published in Proceedings of the National Academy of Sciences of the United States of America at DOI: https://doi.org/10.1073/pnas.2506846122