Broken DNA—be it a gap, a nick or a double strand break —is a hallmark of cancerous or aging cells. But once key kinases and their regulators detect DNA damage, a molecular cascade swings into action, triggering posttranscriptional changes in proteins that eventually spur enzymes, such as ligases, to repair the damage and facilitate further replication. Until recently, little was known about exactly how mammalian cells sense DNA damage and coordinate these responses and which molecules act to set things right.
By the mid-1990s, researchers had explored the DNA damage response (DDR) using simple model organisms, such as yeast, and found that DDR was a signal transduction pathway with two kinases, namely ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related), orchestrating a suite of phosphorylation events. About 100 proteins were implicated in the response, and about 25 of those were known to be actual kinase phosphorylation substrates.
Then Stephen ...
