Regulation of USP7/HAUSP in response to DNA damage

The ataxia-telangiectasia mutated (ATM) protein kinase is widely accepted to play a key role in the DNA damage response, in particular in the signaling of radiationinduced DNA double-strand breaks. In this regard, ATM activates a number of cell cycle checkpoints to delay DNA replication and ensure the correct processing of the damaged DNA. This is achieved both directly, through phosphorylation of p53 at Ser15, and indirectly, via phosphorylation of Mdm2, Mdmx and Chk2, which subsequently control the cellular levels of the p53 tumor suppressor. Consequently, this causes activation of either a G 1 cell cycle delay, to allow DNA repair processes to be completed before DNA replication, or the initiation of the apoptotic pathway in the case of excessive DNA damage. ATM also plays a key role in the activation of S-phase, as well as G 2 /M-phase arrest via phosphorylation of BRCA1, SMC1, FANCD2 and many other substrates (reviewed in ref. 4) and was proved to be activated and thus regulate some of its targets in response to oxidative stress. In total, more than several hundred ATM substrates were identified in global proteome screening in cells subjected to IR, which include a number of transcription factors, proteins that sense and transmit DNA damage signals as well as those that mediate chromatin remodeling, DNA replication, mitosis and other cellular processes Despite the extensive research performed in the field of discovering new ATM substrates and their functions, there are still more intriguing discoveries to come. In this context, Khoronenkova et al. recently proposed a mechanism as to how the IR-induced DNA damage Regulation of USP7/HAUSP in response to DNA damage Yet another role for ATM