Mutations of the Huntington's disease protein impact on the ATM-dependent signaling and repair pathways of the radiation-induced DNA double-strand breaks: corrective effect of statins and bisphosphonates

Mol Neurobiol. 2014 Jun;49(3):1200-11. doi: 10.1007/s12035-013-8591-7. Epub 2013 Nov 26.


Huntington's disease (HD) is a neurodegenerative syndrome caused by mutations of the IT15 gene encoding for the huntingtin protein. Some research groups have previously shown that HD is associated with cellular radiosensitivity in quiescent cells. However, there is still no mechanistic model explaining such specific clinical feature. Here, we examined the ATM-dependent signaling and repair pathways of the DNA double-strand breaks (DSB), the key damage induced by ionizing radiation, in human HD skin fibroblasts. Early after irradiation, quiescent HD fibroblasts showed an abnormally low rate of recognized DSB managed by non-homologous end-joining reflected by a low yield of nuclear foci formed by phosphorylated H2AX histones and by 53BP1 protein. Furthermore, HD cells elicited a significant but moderate yield of unrepaired DSB 24 h after irradiation. Irradiated HD cells also presented a delayed nucleo-shuttling of phosphorylated forms of the ATM kinase, potentially due to a specific binding of ATM to mutated huntingtin in the cytoplasm. Our results suggest that HD belongs to the group of syndromes associated with a low but significant defect of DSB signaling and repair defect associated with radiosensitivity. A combination of biphosphonates and statins complements these impairments by facilitating the nucleo-shuttling of ATM, increasing the yield of recognized and repaired DSB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cells, Cultured
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Breaks, Double-Stranded / radiation effects*
  • DNA Repair / drug effects
  • DNA Repair / genetics
  • Diphosphonates / pharmacology*
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / physiology
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Male
  • Mutation / drug effects
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics*


  • Diphosphonates
  • HTT protein, human
  • Huntingtin Protein
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Nerve Tissue Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins