Smoking and Carcinoma of the Lung

1950/09/30 by Richard Doll, A. Bradford Hill, A. B. Hill · 39 citations
Medicine · Biochemistry, Genetics and Molecular Biology · #Genetic factors in colorectal cancer #DNA Repair Mechanisms

paper · pdf · doi:10.1136/bmj.2.4682.739

Abstract

DNA repair is crucial for genome stability in the developing cortex, as somatic de novo mutations cause neurological disorders. However, how DNA repair contributes to neuronal development is largely unknown. To address this issue, we studied the spatiotemporal roles of DNA polymerase β (Polβ), a key enzyme in DNA base excision repair pathway, in the developing cortex using distinct forebrain-specific conditional knock-out mice, Emx1-Cre/Polβfl/fl and Nex-Cre/Polβfl/fl mice. Polβ expression was absent in both neural progenitors and postmitotic neurons in Emx1-Cre/Polβfl/fl mice, whereas only postmitotic neurons lacked Polβ expression in Nex-Cre/Polβfl/fl mice. We found that DNA double-strand breaks (DSBs) were frequently detected during replication in cortical progenitors of Emx1-Cre/Polβfl/fl mice. Increased DSBs remained in postmitotic cells, which resulted in p53-mediated neuronal apoptosis. This neuronal apoptosis caused thinning of the cortical plate, although laminar structure was normal. In addition, accumulated DSBs also affected growth of corticofugal axons but not commissural axons. These phenotypes were not observed in Nex-Cre/Polβfl/fl mice. Moreover, cultured Polβ-deficient neural progenitors exhibited higher sensitivity to the base-damaging agent methylmethanesulfonate, resulting in enhanced DSB formation. Similar damage was found by vitamin C treatment, which induces TET1-mediated DNA demethylation via 5-hydroxymethylcytosine. Together, genome stability mediated by Polβ-dependent base excision repair is crucial for the competence of neural progenitors, thereby contributing to neuronal differentiation in cortical development. SIGNIFICANCE STATEMENT DNA repair is crucial for development of the nervous system. However, how DNA polymerase β (Polβ)-dependent DNA base excision repair pathway contributes to the process is still unknown. We found that loss of Polβ in cortical progenitors rather than postmitotic neurons led to catastrophic DNA double-strand breaks (DSBs) during replication and p53-mediated neuronal apoptosis, which resulted in thinning of the cortical plate. The DSBs also affected corticofugal axon growth in surviving neurons. Moreover, induction of base damage and DNA demethylation intermediates in the genome increased DSBs in cultured Polβ-deficient neural progenitors. Thus, genome stability by Polβ-dependent base excision repair in neural progenitors is required for the viability and differentiation of daughter neurons in the developing nervous system.

Citations

• TOBACCO SMOKING AS A POSSIBLE ETIOLOGIC FACTOR IN BRONCHIOGENIC CARCINOMA

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