title: Neurological disorders associated with DNA strand-break processing enzymes.
abstract: The termini of DNA strand breaks induced by reactive oxygen species or by abortive DNA metabolic intermediates require processing to enable subsequent gap filling and ligation to proceed. The three proteins, tyrosyl DNA-phosphodiesterase 1 (TDP1), aprataxin (APTX) and polynucleotide kinase/phosphatase (PNKP) each act on a discrete set of modified strand-break termini. Recently, a series of neurodegenerative and neurodevelopmental disorders have been associated with mutations in the genes coding for these proteins. Mutations in TDP1 and APTX have been linked to Spinocerebellar ataxia with axonal neuropathy (SCAN1) and Ataxia-ocular motor apraxia 1 (AOA1), respectively, while mutations in PNKP are considered to be responsible for Microcephaly with seizures (MCSZ) and Ataxia-ocular motor apraxia 4 (AOA4). Here we present an overview of the mechanisms of these proteins and how their impairment may give rise to their respective disorders.
authors.affiliation: Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada. Electronic address: bj@ualberta.ca.
authors.forename: Bingcheng
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry, Medical Sciences Building, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada. Electronic address: mark.glover@alberta.ca.
authors.forename: J N Mark
authors.initials: JN
authors.lastname: Glover
authors.affiliation: Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada. Electronic address: mweinfel@ualberta.ca.
authors.forename: Michael
authors.initials: M
authors.lastname: Weinfeld
mesh_terms: D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D065886:Neurodevelopmental Disorders / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism
chemical_list: C438188:APTX protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C530380:PNKP protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; D045643:DNA Repair Enzymes
keywords: Aprataxin; DNA repair; DNA strand breaks; Neurodegeneration; Polynucleotide kinase/phosphatase; Tyrosyl DNA-phosphodiesterase 1