title: Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes.
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.
authors.affiliation: 1] Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmacology and Therapeutics, University of Manitoba and Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Sachin
authors.initials: S
authors.lastname: Katyal
authors.affiliation: 1] Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] GIRC, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Biopharmaceutical Sciences, University of Illinois-Chicago, Rockford, Illinois, USA.
authors.forename: Karin C
authors.initials: KC
authors.lastname: Nitiss
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Downing
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Mikio
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Russell
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, New York, USA.
authors.forename: John H J
authors.initials: JH
authors.lastname: Petrini
authors.affiliation: Department of Biopharmaceutical Sciences, University of Illinois-Chicago, Rockford, Illinois, USA.
authors.forename: John L
authors.identifier: 0000000210134972
authors.initials: JL
authors.lastname: Nitiss
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics; D004264:DNA Topoisomerases, Type I / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D013577:Syndrome
chemical_list: D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human