14-3-3 proteins, FHA domains and BRCT domains in the DNA damage response

DNA Repair (Amst). 2009 Sep 2;8(9):1009-17. doi: 10.1016/j.dnarep.2009.04.004. Epub 2009 May 29.


The DNA damage response depends on the concerted activity of protein serine/threonine kinases and modular phosphoserine/threonine-binding domains to relay the damage signal and recruit repair proteins. The PIKK family of protein kinases, which includes ATM/ATR/DNA-PK, preferentially phosphorylate Ser-Gln sites, while their basophilic downstream effecter kinases, Chk1/Chk2/MK2 preferentially phosphorylate hydrophobic-X-Arg-X-X-Ser/Thr-hydrophobic sites. A subset of tandem BRCT domains act as phosphopeptide binding modules that bind to ATM/ATR/DNA-PK substrates after DNA damage. Conversely, 14-3-3 proteins interact with substrates of Chk1/Chk2/MK2. FHA domains have been shown to interact with substrates of ATM/ATR/DNA-PK and CK2. In this review we consider how substrate phosphorylation together with BRCT domains, FHA domains and 14-3-3 proteins function to regulate ionizing radiation-induced nuclear foci and help to establish the G(2)/M checkpoint. We discuss the role of MDC1 a molecular scaffold that recruits early proteins to foci, such as NBS1 and RNF8, through distinct phosphodependent interactions. In addition, we consider the role of 14-3-3 proteins and the Chk2 FHA domain in initiating and maintaining cell cycle arrest.

Publication types

  • Review

MeSH terms

  • 14-3-3 Proteins / metabolism*
  • Animals
  • Cell Cycle / radiation effects
  • Cell Nucleus / metabolism
  • Cell Nucleus / radiation effects
  • DNA Damage*
  • Humans
  • Protein Structure, Tertiary*
  • Radiation, Ionizing


  • 14-3-3 Proteins