title: Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors.
abstract: 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. Notably, disrupted neurogenesis in TopBP1-depleted tissues was substantially rescued by inactivation of p53 but not of ATM. 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.
authors.affiliation: Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN, USA.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Lee
authors.forename: Sachin
authors.initials: S
authors.lastname: Katyal
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Downing
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Zhao
authors.forename: Helen R
authors.initials: HR
authors.lastname: Russell
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D001921:Brain; D002352:Carrier Proteins / Q000378:metabolism*; D002452:Cell Count; D020552:Comet Assay; D004249:DNA Damage / Q000502:physiology*; D004261:DNA Replication / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; C492846:Topbp1 protein, mouse