Article abstract
Nature Neuroscience 12, 973 - 980 (2009)
Published online: 26 July 2009 | doi:10.1038/nn.2375
The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1
Youngsoo Lee1, Sachin Katyal1, Yang Li1, Sherif F El-Khamisy2,3, Helen R Russell1, Keith W Caldecott2 & Peter J McKinnon1
Abstract
Defective responses to DNA single strand breaks underlie various neurodegenerative diseases. However, the exact role of this repair pathway during the development and maintenance of the nervous system is unclear. Using murine neural-specific inactivation of Xrcc1, a factor that is critical for the repair of DNA single strand breaks, we found a profound neuropathology that is characterized by the loss of cerebellar interneurons. This cell loss was linked to p53-dependent cell cycle arrest and occurred as interneuron progenitors commenced differentiation. Loss of Xrcc1 also led to the persistence of DNA strand breaks throughout the nervous system and abnormal hippocampal function. Collectively, these data detail the in vivo link between DNA single strand break repair and neurogenesis and highlight the diverse consequences of specific types of genotoxic stress in the nervous system.
- Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
- Genome Damage and Stability Unit, University of Sussex, Brighton, UK.
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Correspondence to: Peter J McKinnon1 e-mail: peter.mckinnon@stjude.org
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