title: TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo.
abstract: 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.
authors.affiliation: Department Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Katyal
authors.forename: Sherif F
authors.initials: SF
authors.lastname: el-Khamisy
authors.forename: Helen R
authors.initials: HR
authors.lastname: Russell
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Limei
authors.initials: L
authors.lastname: Ju
authors.forename: Keith W
authors.initials: KW
authors.lastname: Caldecott
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002784:Cholesterol / Q000097:blood; D053904:DNA Breaks, Single-Stranded; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D005260:Female; D005720:Gamma Rays; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007422:Intestines / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012709:Serum Albumin / Q000032:analysis; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D019772:Topotecan / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D012709:Serum Albumin; D019772:Topotecan; D002784:Cholesterol; D006861:Hydrogen Peroxide; D010727:Phosphoric Diester Hydrolases; C524959:Tdp1 protein, mouse; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin