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Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors

The rapid proliferation of progenitors during neurogenesis requires a stringent genomic maintenance program to ensure transmission of genetic fidelity. However the essential factors that govern neural progenitor genome integrity are unknown. Here we report that conditional inactivation of mouse TopB...

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Autores principales: Lee, Youngsoo, Katyal, Sachin, Downing, Susanna M., Zhao, Jingfeng, Russell, Helen R., McKinnon, Peter J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404252/
https://www.ncbi.nlm.nih.gov/pubmed/22522401
http://dx.doi.org/10.1038/nn.3097
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author Lee, Youngsoo
Katyal, Sachin
Downing, Susanna M.
Zhao, Jingfeng
Russell, Helen R.
McKinnon, Peter J.
author_facet Lee, Youngsoo
Katyal, Sachin
Downing, Susanna M.
Zhao, Jingfeng
Russell, Helen R.
McKinnon, Peter J.
author_sort Lee, Youngsoo
collection PubMed
description The rapid proliferation of progenitors during neurogenesis requires a stringent genomic maintenance program to ensure transmission of genetic fidelity. However the essential factors that govern neural progenitor genome integrity are unknown. Here we report that conditional inactivation of mouse TopBP1, a protein linked to DNA replication, and a key activator of the DNA damage response kinase ATR (ataxia telangiectasia and rad3 related) is critical for maintenance of early-born neural progenitors. During cortical development TopBP1 prevented replication-associated DNA damage in Emx1-progenitors which otherwise resulted in profound tissue ablation. Importantly, disrupted neurogenesis in TopBP1-depleted tissues was substantially rescued by p53- but not ATM-inactivation. Our data establish that TopBP1 is essential for preventing replication-associated DNA strand breaks, but is not essential per se for DNA replication. Thus, TopBP1 is crucial for maintaining genome integrity in the early progenitors that drive neurogenesis.
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spelling pubmed-34042522012-12-01 Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors Lee, Youngsoo Katyal, Sachin Downing, Susanna M. Zhao, Jingfeng Russell, Helen R. McKinnon, Peter J. Nat Neurosci Article The rapid proliferation of progenitors during neurogenesis requires a stringent genomic maintenance program to ensure transmission of genetic fidelity. However the essential factors that govern neural progenitor genome integrity are unknown. Here we report that conditional inactivation of mouse TopBP1, a protein linked to DNA replication, and a key activator of the DNA damage response kinase ATR (ataxia telangiectasia and rad3 related) is critical for maintenance of early-born neural progenitors. During cortical development TopBP1 prevented replication-associated DNA damage in Emx1-progenitors which otherwise resulted in profound tissue ablation. Importantly, disrupted neurogenesis in TopBP1-depleted tissues was substantially rescued by p53- but not ATM-inactivation. Our data establish that TopBP1 is essential for preventing replication-associated DNA strand breaks, but is not essential per se for DNA replication. Thus, TopBP1 is crucial for maintaining genome integrity in the early progenitors that drive neurogenesis. 2012-06 /pmc/articles/PMC3404252/ /pubmed/22522401 http://dx.doi.org/10.1038/nn.3097 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Lee, Youngsoo
Katyal, Sachin
Downing, Susanna M.
Zhao, Jingfeng
Russell, Helen R.
McKinnon, Peter J.
Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors
title Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors
title_full Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors
title_fullStr Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors
title_full_unstemmed Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors
title_short Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors
title_sort neurogenesis requires topbp1 to prevent catastrophic replicative dna damage in early progenitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404252/
https://www.ncbi.nlm.nih.gov/pubmed/22522401
http://dx.doi.org/10.1038/nn.3097
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