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PMID: 19633665 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1.

Nature neuroscience ·Vol. 12 ·No. 8 ·2009-08-00 ·Pages 973-80

Lee Y, Katyal S, Li Y, El-Khamisy SF, Russell HR, Caldecott KW, McKinnon PJ

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.

MeSH Terms
Animals Cell Differentiation/genetics Cerebellum/abnormalities,cytology,metabolism DNA Damage/genetics DNA Repair/genetics DNA-Binding Proteins/genetics Down-Regulation/genetics Genes, cdc/physiology Hippocampus/abnormalities,physiopathology Interneurons/metabolism Mice Mice, Knockout Nerve Degeneration/genetics,metabolism,physiopathology Neurogenesis/genetics Stem Cells/metabolism Tumor Suppressor Protein p53/genetics,metabolism X-ray Repair Cross Complementing Protein 1
Chemicals
DNA-Binding Proteins Tumor Suppressor Protein p53 X-ray Repair Cross Complementing Protein 1 Xrcc1 protein, mouse
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Lee Youngsoo
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Katyal Sachin
Li Yang
El-Khamisy Sherif F
Russell Helen R
Caldecott Keith W
McKinnon Peter J
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Article Info
Journal
Nature neuroscience
Abbr.
Nat Neurosci
ISSN
1546-1726
DOI
10.1038/nn.2375
Published
2009-08-00
Epub
2009-00-26
Pages
973-80
Language
English
Region
United States
NLM ID
9809671
PMCID
PMC2831284
Subset
IM
Grants
NINDS NIH HHS · R56 NS037956 · United States
Wellcome Trust · 085284 · United Kingdom
NINDS NIH HHS · R01 NS037956 · United States
Medical Research Council · G0600776 · United Kingdom
NINDS NIH HHS · NS-37956 · United States
NCI NIH HHS · P30 CA021765 · United States
Medical Research Council · G0400959 · United Kingdom
NINDS NIH HHS · R01 NS037956-09 · United States
NCI NIH HHS · P30 CA21765 · United States
NCI NIH HHS · CA-21765 · United States
External Links
PubMed source DOI: 10.1038/nn.2375 PMC Full Text View journal details
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