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Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes

Nature Neuroscience volume 17, pages 813821 (2014) | Download Citation

Abstract

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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Acknowledgements

We thank E. Soans and M. Mishina for assistance with the ICE bioassay, B. Kuzio for general technical assistance, F. Alt (Children's Hospital of Boston) for Prkdc−/− mice, K. Caldecott and S. El-Khamisy (U. Sussex) and R. Klein-Geltink (St. Jude Children's Research Hospital) for helpful discussions and S. Foster (Memorial Sloan-Kettering Cancer Center) for help analyzing the mice. We also thank the St. Jude Children's Research Hospital Animal Resource Center and the Transgenic Core Unit for support with mouse work. P.J.M. is supported by the US National Institutes of Health (NS-37956, CA-96832), the CCSG (P30 CA21765), and the American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital. J.L.N. is supported by the National Cancer Institute (CA52814 and CA82313). J.H.J.P. is supported by the US National Institutes of Health (GM59413), the Geoffrey Beene Foundation and the Goodwin Foundation. Y. Lee is supported by the SRC program (2011-0030833). S.K. is a Neoma Boadway AP Endowed Fellow and is supported by grants from the University of Manitoba, CancerCare Manitoba and a Manitoba Health Research Council Establishment award.

Author information

Affiliations

  1. Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Sachin Katyal
    • , Youngsoo Lee
    • , Susanna M Downing
    • , Yang Li
    • , Mikio Shimada
    • , Jingfeng Zhao
    • , Helen R Russell
    •  & Peter J McKinnon
  2. Department of Pharmacology and Therapeutics, University of Manitoba and Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Manitoba, Canada.

    • Sachin Katyal
  3. GIRC, Ajou University School of Medicine, Suwon, Korea.

    • Youngsoo Lee
  4. Department of Biopharmaceutical Sciences, University of Illinois-Chicago, Rockford, Illinois, USA.

    • Karin C Nitiss
    •  & John L Nitiss
  5. Molecular Biology Program, Memorial Sloan-Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, New York, USA.

    • John H J Petrini

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Contributions

S.K. and P.J.M. conceived and planned all of the experiments and produced the final version of the manuscript. S.K. performed all of the experiments with contributions from K.C.N. (in vitro TDP1 cleavage assay), Y. Lee, M.S. and H.R.R. (generation of the mutant mice and additional technical support), S.M.D. and Y. Li (processing tissue for ICE bioassay and mouse colony management), and J.Z. (AtmNes-cre and ATMi immunoblotting experiments). J.H.J.P. contributed critical reagents and experimental results. J.L.N. contributed to experimental design and the interpretation of results and the preparation of the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sachin Katyal or Peter J McKinnon.

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DOI

https://doi.org/10.1038/nn.3715

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