Journal
NATURE NEUROSCIENCE
Volume 17, Issue 6, Pages 813-821Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.3715
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Funding
- St. Jude Children's Research Hospital Animal Resource Center
- Transgenic Core Unit
- US National Institutes of Health [NS-37956, CA-96832, GM59413]
- CCSG [P30 CA21765]
- American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital
- National Cancer Institute [CA52814, CA82313]
- Geoffrey Beene Foundation
- Goodwin Foundation
- SRC program [2011-0030833]
- University of Manitoba, CancerCare Manitoba
- Manitoba Health Research Council Establishment award
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DNA damage is considered to be a prime factor in several spinocerebellar neurodegenerative diseases; however, the DNA lesions underpinning disease etiology are unknown. We observed the endogenous accumulation of pathogenic topoisomerase-1 (Top1)-DNA cleavage complexes (Top1ccs) in murine models of ataxia telangiectasia and spinocerebellar ataxia with axonal neuropathy 1. We found that the defective DNA damage response factors in these two diseases cooperatively modulated Top1cc turnover in a non-epistatic and ATM kinase-independent manner. Furthermore, coincident neural inactivation of ATM and DNA single-strand break repair factors, including tyrosyl-DNA phosphodiesterase-1 or XRCC1, resulted in increased Top1cc formation and excessive DNA damage and neurodevelopmental defects. Notably, direct Top1 poisoning to elevate Top1cc levels phenocopied the neuropathology of the mouse models described above. Our results identify a critical endogenous pathogenic lesion associated with neurodegenerative syndromes arising from DNA repair deficiency, indicating that genome integrity is important for preventing disease in the nervous system.
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