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  • The EMBO Journal (2007) 26, 4720 - 4731
  • doi:10.1038/sj.emboj.7601869

Published online: 4 October 2007

TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo

Sachin Katyal1,a, Sherif F El-Khamisy2,3,a, Helen R Russell1, Yang Li1, Limei Ju2, Keith W Caldecott2 and Peter J McKinnon1

  1. Department Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA
  2. Genome Damage and Stability Center, University of Sussex, Falmer, Brighton, UK
  3. Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

Correspondence to:

Keith W Caldecott, Genome Damage and Stability Center, University of Sussex, Falmer, Brighton BN1 9RQ, UK. Tel.: +44 1323 877519; Fax: +44 1323 678121; E-mail: k.w.caldecott@sussex.ac.uk

Peter J McKinnon, Department Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA. Tel.: +1 901 495 2700; Fax: +1 901 526 2907; E-mail: peter.mckinnon@stjude.org

aThese authors contributed equally to this work

Received 10 April 2007; Accepted 5 September 2007

Defective Tyrosyl-DNA phosphodiesterase 1 (TDP1) can cause spinocerebellar ataxia with axonal neuropathy (SCAN1), a neurodegenerative syndrome associated with marked cerebellar atrophy and peripheral neuropathy. Although SCAN1 lymphoblastoid cells show pronounced defects in the repair of chromosomal single-strand breaks (SSBs), it is unknown if this DNA repair activity is important for neurons or for preventing neurodegeneration. Therefore, we generated Tdp1-/- mice to assess the role of Tdp1 in the nervous system. Using both in vitro and in vivo assays, we found that cerebellar neurons or primary astrocytes derived from Tdp1-/- mice display an inability to rapidly repair DNA SSBs associated with Top1–DNA complexes or oxidative damage. Moreover, loss of Tdp1 resulted in age-dependent and progressive cerebellar atrophy. Tdp1-/- mice treated with topotecan, a drug that increases levels of Top1–DNA complexes, also demonstrated significant loss of intestinal and hematopoietic progenitor cells. These data indicate that TDP1 is required for neural homeostasis, and reveal a widespread requisite for TDP1 function in response to acutely elevated levels of Top1-associated DNA strand breaks.

  • Keywords:

    • DNA repair,
    • neurodegeneration,
    • single-strand breaks,
    • TDP1,
    • topoisomerase 1