Polß Maintains Genomic Integrity During Brain Development

A team led by The University of Osaka has identified the DNA repair enzyme Polβ as a key player in protecting the developing brain from harmful genetic changes. Their study, published in the Proceedings of the National Academy of Sciences, reveals that Polβ is essential for preventing small insertions and deletions of DNA, known as indels, especially near CpG sites—regions of the genome highly involved in gene regulation. The research demonstrates that absence of Polβ leads to a striking increase in the frequency of indels, which could contribute to the onset of neurodevelopmental disorders.

The human brain develops through complex processes governed by detailed genetic instructions. DNA damage, however, can arise during this period, and if not properly repaired, it may result in lasting mutations within nerve cells. While the occurrence of mutations in developing nerve cells has been known, the mechanisms controlling their prevention have not been thoroughly understood until now.

In this study, the team found that Polβ plays an indispensable role in preventing the accumulation of indel mutations around CpG sites during brain development. These CpG regions undergo dynamic changes in methylation—a chemical modification of DNA—while the brain develops. The findings show that Polβ actively repairs DNA damage induced by the removal of methyl groups in these areas, acting as a genomic safeguard. Without Polβ, indel mutations at CpG sites increase approximately ninefold, emphasizing the enzyme’s protective effect.

This new evidence uncovers a previously unrecognized function of Polβ in maintaining genome integrity in the developing brain. The data indicate that shortcomings in Polβ activity could lead to neurodevelopmental problems as a result of unchecked mutations. According to the research group, their work provides valuable molecular insight into the origins of brain developmental disorders and may inform future approaches to prevention and intervention.

Lead author Noriyuki Sugo explained, “Our study is the first in the world to demonstrate the crucial role of Polβ in preventing mutations in developing nerve cells.” He adds, “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 intends to delve deeper into how Polβ dysfunction might be linked to specific neurodevelopmental conditions.