Molecular basis of ataxia telangiectasia and related diseases

Acta Pharmacol Sin. 2005 Aug;26(8):897-907. doi: 10.1111/j.1745-7254.2005.00165.x.

Abstract

Ataxia telangiectasia (AT) is a rare human disease characterized by extreme cellular sensitivity to radiation and a predisposition to cancer, with a hallmark of onset in early childhood. Several human diseases also share similar symptoms with AT albeit with different degrees of severity and different associated disorders. While all AT patients contain mutations in the AT-mutated gene (ATM), most other AT-like disorders are defective in genes encoding an MRN protein complex consisting of Mre11, Rad50 and Nbs1. Both ATM and MRN function as cellular sensors to DNA double-strand breaks, which lead to the recruitment and phosphorylation of an array of substrate proteins involved in DNA repair, apoptosis and cell-cycle checkpoints, as well as gene regulation, translation initiation and telomere maintenance. ATM is a member of the family of phosphatidylinositol 3-kinase-like protein kinases (PIKK), and the discovery of many ATM substrates provides the underlying mechanisms of heterologous symptoms among AT patients. This review article focuses on recent findings related to the initial recognition of double-strand breaks by ATM and MRN, as well as a DNA-dependent protein kinase complex consisting of the heterodimer Ku70/Ku80 and its catalytic subunit DNA-PKcs, another member of PIKK. This possible interaction suggests that a much greater complex is involved in sensing, transducing and co-ordinating cellular events in response to genome instability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Acid Anhydride Hydrolases
  • Antigens, Nuclear / metabolism
  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia / metabolism
  • Ataxia Telangiectasia / pathology
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • DNA Damage
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Humans
  • Ku Autoantigen
  • MRE11 Homologue Protein
  • Mutation*
  • Nijmegen Breakage Syndrome / genetics
  • Nijmegen Breakage Syndrome / metabolism
  • Nijmegen Breakage Syndrome / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Antigens, Nuclear
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MRE11 protein, human
  • NBN protein, human
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • MRE11 Homologue Protein
  • Acid Anhydride Hydrolases
  • Rad50 protein, human
  • Xrcc6 protein, human
  • Ku Autoantigen
  • DNA Repair Enzymes