| First Author | Katyal S | Year | 2007 |
| Journal | EMBO J | Volume | 26 |
| Issue | 22 | Pages | 4720-31 |
| PubMed ID | 17914460 | Mgi Jnum | J:127605 |
| Mgi Id | MGI:3763978 | Doi | 10.1038/sj.emboj.7601869 |
| Citation | Katyal S, et al. (2007) TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo. EMBO J 26(22):4720-31 |
| abstractText | 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. |
