Mohammad Duaa H, Yaffe Michael B
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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.
DNA损伤反应依赖于蛋白质丝氨酸/苏氨酸激酶和模块化磷酸丝氨酸/苏氨酸结合结构域的协同作用，以传递损伤信号并招募修复蛋白。蛋白激酶的PIKK家族，包括ATM/ATR/DNA-PK，优先磷酸化Ser-Gln位点，而其嗜碱性下游效应激酶Chk1/Chk2/MK2优先磷酸化疏水-X-Arg-X-X-Ser/Thr-疏水位点。串联BRCT结构域的一个子集作为磷酸肽结合模块，在DNA损伤后与ATM/ATR/DNA-PK底物结合。相反，14-3-3蛋白与Chk1/Chk2/MK2的底物相互作用。FHA结构域已被证明与ATM/ATR/DNA-PK和CK2的底物相互作用。在这篇综述中，我们考虑底物磷酸化如何与BRCT结构域、FHA结构域和14-3-3蛋白共同作用，以调节电离辐射诱导的核灶并帮助建立G(2)/M期检查点。我们讨论了MDC1的作用，它是一种分子支架，通过独特的磷酸依赖性相互作用将早期蛋白招募到病灶，如NBS1和RNF8。此外，我们考虑了14-3-3蛋白和Chk2 FHA结构域在启动和维持细胞周期停滞中的作用。
