DNA is constantly damaged by various environmental agents and metabolic processes. To maintain genome integrity and prevent mutations, cells have evolved complex DNA damage response (DDR) pathways. A key step in the DDR is the activation of the kinase ataxia-telangiectasia mutated (ATM). ATM phosphorylates numerous substrates to orchestrate DNA repair and cell cycle checkpoints.

Researchers at the Francis Crick Institute have now mapped the signalling network downstream of ATM using chemical inhibitors, quantitative mass spectrometry and genetic approaches. These studies revealed critical roles for the kinase CHK2 and the ubiquitin ligase RNF8 for the DNA damage signalling of different ATM substrates.

One interesting finding of the study is the hierarchical phosphorylation of ATM substrates. Some substrates, such as the checkpoint kinase CHK2, are directly phosphorylated by ATM, while others, such as the histone variant H2AX, are phosphorylated by downstream kinases activated by ATM. This hierarchical phosphorylation ensures that different DNA repair and cell cycle checkpoint responses are activated in a coordinated manner.

Together, this work provides a detailed understanding of the ATM signalling network and how it coordinates DNA repair and cell cycle checkpoints to maintain genome integrity. This knowledge could lead to the development of new therapies for cancer and other diseases characterized by DNA damage.