Molecular underpinnings of Aprataxin RNA/DNA deadenylase function and dysfunction in neurological disease

Matthew J. Schellenberg, Percy P. Tumbale, R. Scott Williams

Research output: Contribution to journalReview articlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)157-165
Number of pages9
JournalProgress in Biophysics and Molecular Biology
Volume117
Issue number2-3
DOIs
StatePublished - Mar 1 2015

Keywords

  • AOA1
  • Aprataxin
  • Aptx
  • DNA damage response
  • DNA ligase
  • Neurodegenerative disease

ASJC Scopus subject areas

  • Biophysics
  • Molecular Biology

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