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

Title14-3-3 proteins, FHA domains and BRCT domains in the DNA damage response.
Publication TypeJournal Article
Year of Publication2009
AuthorsMohammad, DH, Yaffe, MB
JournalDNA Repair (Amst)
Date Published2009 Sep 2
Keywords14-3-3 Proteins, Animals, Cell Cycle, Cell Nucleus, DNA Damage, Humans, Protein Structure, Tertiary, Radiation, Ionizing

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.

Alternate JournalDNA Repair (Amst.)
PubMed ID19481982
PubMed Central IDPMC3263375
Grant ListR01 ES015339-05 / ES / NIEHS NIH HHS / United States
R01 GM060594-09 / GM / NIGMS NIH HHS / United States
U54 CA112967-07 / CA / NCI NIH HHS / United States