Defective ATM-Kap-1-mediated chromatin remodeling impairs DNA repair and accelerates senescence in progeria mouse model

Aging Cell. 2013 Apr;12(2):316-8. doi: 10.1111/acel.12035. Epub 2012 Dec 21.

Abstract

ATM-mediated phosphorylation of KAP-1 triggers chromatin remodeling and facilitates the loading and retention of repair proteins at DNA lesions. Mouse embryonic fibroblasts (MEFs) derived from Zmpste24(-/-) mice undergo early senescence, attributable to delayed recruitment of DNA repair proteins. Here, we show that ATM-Kap-1 signaling is compromised in Zmpste24(-/-) MEFs, leading to defective DNA damage-induced chromatin remodeling. Knocking down Kap-1 rescues impaired chromatin remodeling, defective DNA repair and early senescence in Zmpste24(-/-) MEFs. Thus, ATM-Kap-1-mediated chromatin remodeling plays a critical role in premature aging, carrying significant implications for progeria therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Chromatin Assembly and Disassembly*
  • DNA / metabolism*
  • DNA Damage
  • DNA Repair*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Gene Expression Regulation
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Metalloendopeptidases / deficiency
  • Metalloendopeptidases / genetics
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Progeria / genetics*
  • Progeria / metabolism
  • Progeria / pathology
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Tripartite Motif-Containing Protein 28
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Membrane Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • DNA
  • Trim28 protein, mouse
  • Tripartite Motif-Containing Protein 28
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases
  • Metalloendopeptidases
  • Zmpste24 protein, mouse