Summary: A new study shows that the DNA repair enzyme Polβ plays a vital role in protecting the developing brain from harmful mutations. Researchers found that without Polβ, insertion-deletion mutations near CpG sites rose sharply, threatening genetic stability during crucial stages of brain growth.
These regions are essential for regulating gene activity and are especially vulnerable during DNA demethylation. The findings shed light on the molecular roots of neurodevelopmental disorders and point to potential new avenues for prevention and treatment.
Key Facts
- Polβ Function: Repairs DNA damage during brain development, preventing harmful indel mutations.
- Mutation Increase: Loss of Polβ causes a ninefold rise in indel mutations at CpG sites.
- Health Impact: Findings link DNA repair deficits to neurodevelopmental disorders, with implications for cancer and aging research.
Source: Osaka University
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.
About this genetics and neurology research news
Author: Saori Obayashi
Source: Osaka University
Contact: Saori Obayashi – Osaka University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons” by Noriyuki Sugo et al. PNAS
Abstract
DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons
Somatic mutations in cortical neurons have been implicated in psychiatric disorders. While endogenous DNA damage and repair errors are potential contributors to these mutations during development, the underlying mutagenic mechanism remains unclear.
Here, we investigated somatic mutations in immature cortical neurons using mouse somatic cell nuclear transfer-derived embryonic stem cells and whole-genome sequencing. Insertions and deletions (indels) were commonly observed in both repeat and nonrepeat sequences in wild-type cells.
The loss of DNA polymerase β (Polβ), an enzyme involved in gap-filling during base excision repair and Ten-Eleven Translocation (TET)-mediated active DNA demethylation, in neural progenitor cells increased indel frequency by ~ninefold at cytosine-phosphate-guanine (CpG) dinucleotides and raised the frequency of structural variants by ~fivefold.
These mutations were enriched in neuronal genes, leading to frameshift mutations, amino acid insertions/deletions, and the gain and loss of CpG sites in regulatory regions.
Our findings suggest that Polβ preferentially repairs DNA lesions generated at CpG sites by TET-mediated active demethylation, thereby suppressing the mutagenesis that accompanies neuronal gene activation during cortical development.