Neurological disorders associated with DNA strand-break processing enzymes

Mech Ageing Dev. 2017 Jan;161(Pt A):130-140. doi: 10.1016/j.mad.2016.07.009. Epub 2016 Jul 25.


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.

Keywords: Aprataxin; DNA repair; DNA strand breaks; Neurodegeneration; Polynucleotide kinase/phosphatase; Tyrosyl DNA-phosphodiesterase 1.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Breaks, Double-Stranded*
  • DNA Repair Enzymes* / genetics
  • DNA Repair Enzymes* / metabolism
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Heredodegenerative Disorders, Nervous System* / genetics
  • Heredodegenerative Disorders, Nervous System* / metabolism
  • Humans
  • Mutation*
  • Neurodevelopmental Disorders* / genetics
  • Neurodevelopmental Disorders* / metabolism
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / metabolism
  • Phosphoric Diester Hydrolases* / genetics
  • Phosphoric Diester Hydrolases* / metabolism
  • Phosphotransferases (Alcohol Group Acceptor)* / genetics
  • Phosphotransferases (Alcohol Group Acceptor)* / metabolism


  • APTX protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins
  • PNKP protein, human
  • Phosphotransferases (Alcohol Group Acceptor)
  • Phosphoric Diester Hydrolases
  • TDP1 protein, human
  • DNA Repair Enzymes