Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease.
Fairweather, Emma E
Waddell, Ian D
AffiliationGenome 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
MetadataShow full item record
AbstractThe 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.
CitationMechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease. 2018, 37(14): EMBO J
JournalThe EMBO Journal
- Structure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease.
- Authors: Tumbale P, Appel CD, Kraehenbuehl R, Robertson PD, Williams JS, Krahn J, Ahel I, Williams RS
- Issue date: 2011 Oct 9
- Molecular underpinnings of Aprataxin RNA/DNA deadenylase function and dysfunction in neurological disease.
- Authors: Schellenberg MJ, Tumbale PP, Williams RS
- Issue date: 2015 Mar
- Aprataxin resolves adenylated RNA-DNA junctions to maintain genome integrity.
- Authors: Tumbale P, Williams JS, Schellenberg MJ, Kunkel TA, Williams RS
- Issue date: 2014 Feb 6
- Early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ataxia with oculomotor apraxia 1.
- Authors: Tada M, Yokoseki A, Sato T, Makifuchi T, Onodera O
- Issue date: 2010
- The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates.
- Authors: Ahel I, Rass U, El-Khamisy SF, Katyal S, Clements PM, McKinnon PJ, Caldecott KW, West SC
- Issue date: 2006 Oct 12