title: Molecular underpinnings of Aprataxin RNA/DNA deadenylase function and dysfunction in neurological disease.
abstract: Eukaryotic DNA ligases seal DNA breaks in the final step of DNA replication and repair transactions via a three-step reaction mechanism that can abort if DNA ligases encounter modified DNA termini, such as the products and repair intermediates of DNA oxidation, alkylation, or the aberrant incorporation of ribonucleotides into genomic DNA. Such abortive DNA ligation reactions act as molecular checkpoint for DNA damage and create 5'-adenylated nucleic acid termini in the context of DNA and RNA-DNA substrates in DNA single strand break repair (SSBR) and ribonucleotide excision repair (RER). Aprataxin (APTX), a protein altered in the heritable neurological disorder Ataxia with Oculomotor Apraxia 1 (AOA1), acts as a DNA ligase "proofreader" to directly reverse AMP-modified nucleic acid termini in DNA- and RNA-DNA damage responses. Herein, we survey APTX function and the emerging cell biological, structural and biochemical data that has established a molecular foundation for understanding the APTX mediated deadenylation reaction, and is providing insights into the molecular bases of APTX deficiency in AOA1.
authors: Genome Integrity and Structural Biology Laboratory, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, 27709, USA.
authors: Matthew J
authors: MJ
authors: Schellenberg
authors: Genome Integrity and Structural Biology Laboratory, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, 27709, USA.
authors: Percy P
authors: PP
authors: Tumbale
authors: Genome Integrity and Structural Biology Laboratory, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, 27709, USA.
authors: R Scott
authors: RS
authors: Williams
mesh_terms: D000818:Animals; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D005095:Exoribonucleases / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D012313:RNA / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D020754:Spinocerebellar Ataxias / Q000151:congenital* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C438188:APTX protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012313:RNA; D004247:DNA; D005095:Exoribonucleases
keywords: AOA1; Aprataxin; Aptx; DNA damage response; DNA ligase; Neurodegenerative disease
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