Zinc finger protein 668 interacts with Tip60 to promote H2AX acetylation after DNA damage

Cell Cycle. 2013 Jul 1;12(13):2033-41. doi: 10.4161/cc.25064. Epub 2013 Jun 6.


Many tumor suppressors play an important role in the DNA damage pathway. Zinc finger protein 668 (ZNF668) has recently been identified as one of the potential tumor suppressors in breast cancer, but its function in DNA damage response is unknown. Herein, we report that ZNF668 is a regulator of DNA repair. ZNF668 knockdown impairs cell survival after DNA damage without affecting the ATM/ATR DNA-damage signaling cascade. However, recruitment of repair proteins to DNA lesions is decreased. In response to IR, ZNF668 knockdown reduces Tip60-H2AX interaction and impairs IR-induced histone H2AX hyperacetylation, thus impairing chromatin relaxation. Impaired chromatin relaxation causes decreased recruitment of repair proteins to DNA lesions, defective homologous recombination (HR) repair and impaired cell survival after IR. In addition, ZNF668 knockdown decreased RPA phosphorylation and its recruitment to DNA damage foci in response to UV. In both IR and UV damage responses, chromatin relaxation counteracted the impaired loading of repair proteins and DNA repair defects in ZNF668-deficient U2OS cells, indicating that impeded chromatin accessibility at sites of DNA breaks caused the DNA repair defects observed in the absence of ZNF668. Our findings suggest that ZNF668 is a key molecule that links chromatin relaxation with DNA damage response in DNA repair control.

Keywords: DNA damage repair; H2AX acetylation; Tip60; ZNF668.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cell Line, Tumor
  • Cell Survival
  • Chromatin Assembly and Disassembly
  • DNA Breaks, Double-Stranded
  • DNA Damage
  • Histone Acetyltransferases / metabolism*
  • Histones / metabolism*
  • Humans
  • Lysine Acetyltransferase 5
  • Protein Processing, Post-Translational*
  • Rad51 Recombinase / metabolism
  • Recombinational DNA Repair
  • Replication Protein A / metabolism
  • Tumor Suppressor Proteins / metabolism*


  • H2AX protein, human
  • Histones
  • RPA1 protein, human
  • Replication Protein A
  • Tumor Suppressor Proteins
  • ZNF668 protein, human
  • Histone Acetyltransferases
  • KAT5 protein, human
  • Lysine Acetyltransferase 5
  • RAD51 protein, human
  • Rad51 Recombinase