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    Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease.

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    Authors
    Tumbale, P
    Schellenberg, M
    Mueller, G
    Fairweather, Emma E
    Watson, Mandy
    Little, J
    Krahn, J
    Waddell, Ian D
    London, R
    Williams, R
    Affiliation
    Genome Integrity and Structural Biology Laboratory, Department of Health and Human Services, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, NC, USA
    Issue Date
    2018-07-13
    
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    Abstract
    The failure of DNA ligases to complete their catalytic reactions generates cytotoxic adenylated DNA strand breaks. The APTX RNA-DNA deadenylase protects genome integrity and corrects abortive DNA ligation arising during ribonucleotide excision repair and base excision DNA repair, and APTX human mutations cause the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1). How APTX senses cognate DNA nicks and is inactivated in AOA1 remains incompletely defined. Here, we report X-ray structures of APTX engaging nicked RNA-DNA substrates that provide direct evidence for a wedge-pivot-cut strategy for 5'-AMP resolution shared with the alternate 5'-AMP processing enzymes POLβ and FEN1. Our results uncover a DNA-induced fit mechanism regulating APTX active site loop conformations and assembly of a catalytically competent active center. Further, based on comprehensive biochemical, X-ray and solution NMR results, we define a complex hierarchy for the differential impacts of the AOA1 mutational spectrum on APTX structure and activity. Sixteen AOA1 variants impact APTX protein stability, one mutation directly alters deadenylation reaction chemistry, and a dominant AOA1 variant unexpectedly allosterically modulates APTX active site conformations.
    Citation
    Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease. 2018, 37(14): EMBO J
    Journal
    The EMBO Journal
    URI
    http://hdl.handle.net/10541/621159
    DOI
    10.15252/embj.201798875
    PubMed ID
    29934293
    Type
    Article
    Language
    en
    ISSN
    1460-2075
    ae974a485f413a2113503eed53cd6c53
    10.15252/embj.201798875
    Scopus Count
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    All Paterson Institute for Cancer Research

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