DNA is the computer code that programs every event in the body. Despite the importance of DNA fidelity, as the body develops, cells grow and replicate, DNA is constantly turned around. This repeated process can compromise the DNA, which is why the body has many DNA repair proteins. Using mice, scientists at the University of Osaka report a defect in a type of machinery, DNA polymerase beta (Polβ), which causes underdevelopment of the cerebral cortex and the axonal network. The results could help explain cortical developmental disorders, such as autism and microcephaly. Researcher Noriyuki Sugo, an expert in the study of polβ in brain development, described the objectives: “Polβ is responsible for the repair of DNA damage in the brain, because many neurological disorders are associated with de novo mutations, we wanted to study the loss of Polβ affects neuronal development We have found evidence that Polβ plays a role in brain development but not in other organs and that its defect causes catastrophic double strand breaks in DNA (DSB) and subsequent cell death in some regions of the cortex in development path “.
These regions represent one of the early stages of cortical development and the generation of cortical neurons is crucial for a proper neural network. Sugo and his team prepared deficient mutant mice in Polβ. These mice showed a large number of DSBs in neural progenitors, stem cells that eventually produce neurons. As a result, many immature neurons went to die through apoptosis. In addition, the mice showed defects in the development of a specific brain anatomy and the growth of axons in specific cell types, suggesting both underdevelopment of the cortex and neural networks. Well, the Polβ deficiency led to greater cell death in deeper layers than the upper layers of the cortex. The deeper layers were thinner and the deeper layer neurons were marked by a higher rate of DSB. The neurons formed in these layers are considered essential for the early stages of the neural network. Therefore, even if the cells manage to escape death, the brain circuit is probably compromised. Finally, a correct development depends on genetic and epigenetic factors.
Polβ’s correction of DNA damage is an example of genetic regulation. Furthermore, the researchers found that DNA demethylation, an example of epigenetic regulation, is also abnormal in mice deficient in Polβ. This is not the first study on the role of Polβ in brain development. Dr. Sugo and his team, in collaboration with other researchers, have returned to his first job in 2000. Over there he has published a paper that demonstrates that mice with Polβ anomalies died early in life with numerous nerve abnormalities. So in the same mice, the deletion of p53 (the famous gene of death involved in cancer) could save the death of the mice, but not correct the defects of the brain. The opposite effect was found by removing another gene, PARP-1, a protein that is involved in DNA repair. The DNA polymerase β (Polβ), a main component of the base removal pathway (BER), has been shown to be involved in the development of the nervous system rather than in that of other organs. An intriguing question is how these DNA repair enzymes, even if simple, work in normal brain development.
The BER pathway is involved in the active process of DNA demethylation, which is necessary for the epigenetic regulation of gene expression. However, as the PolÎ²-dependent BER contributes to the development of the nervous system remains unknown. Among the results, artificially causing DNA damage (with the MMS carcinogen), the base damage is often converted into DSB during replication in nerve-free nerve progenitors. This result suggests that the Polbeta-dependent BER is necessary for the process of DNA demethylation in neural progenitors, thus contributing to their expertise in becoming adult neurons. Overall, the prof. Sugo argues that the results are a clear proof of the importance of Polβ on proper gene expression in cortical development, providing a new target for the study of syndromes and associated disorders. He concludes: “The brain is actively constructed in embryonic stages: the neural progenitors produce many neurons and their DNA is constantly processed. Thus, defects in the polβ function could be a new objective to explain the disturbances of the development of the cortex”.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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