Beyond ATM: The protein kinase landscape of the DNA damage response

The DNA of all organisms is constantly subjected to damaging agents, both exogenous and endogenous. One extremely harmful lesion is the double-strand break (DSB), which activates a massive signaling network – the DNA damage response (DDR). The chief activator of the DSB response is the ATM protein kinase, which phosphorylates numerous key players in its various branches. Recent phosphoproteomic screens have extended the scope of damage-induced phosphorylations beyond the direct ATM substrates. We review the evidence for the involvement of numerous other protein kinases in the DDR, obtained from documentation of specific pathways as well as high-throughput screens. The emerging picture of the protein phosphorylation landscape in the DDR broadens the current view on the role of this protein modification in the maintenance of genomic stability. Extensive cross-talk between many of these protein kinases forms an interlaced signaling network that spans numerous cellular processes. Versatile protein kinases in this network affect pathways that are different from those they have been identified with to date. The DDR appears to be one of the most extensive signaling responses to cellular stimuli.