ATM and ATR

Abstract

What are ATM and ATR? Ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR) are members of the phosphatidyl-inositol 3-kinase (PI 3-kinase) like family of protein kinases (PIKKs). These large proteins – predicted molecular masses for ATM and ATR are 351kDa and 301kDa, respectively – are involved in cellular responses to DNA damage. Don't ever say… That ATM and ATR phosphorylate lipids! Despite a marked similarity between their carboxy-terminal kinase domains and those of PI 3-kinases, ATM and ATR seem to phosphorylate proteins exclusively. Not to be confused with… Cash dispensers or the anthrax toxin receptor! What do ATM and ATR do in the cell? To maintain genomic stability in the face of constant exposure to exogenous and endogenous DNA-damaging agents, all eukaryotic cells contain elaborate, highly conserved pathways to sense, signal and repair DNA damage. ATM and ATR act near the top of these signalling networks. Their role here is so important that they have been described as ‘sentries at the gate of genome stability’. But what exactly do they do? DNA damage caused by ionising radiation (double-strand DNA breaks) somehow activates the kinase activity of ATM (see below). ATR kinase activity is activated primarily in response to a different set of DNA lesions, including those caused by UV light, and in response to stalled replication forks. Once activated, ATM and ATR phosphorylate an overlapping set of DNArepair/checkpoint targets. For ATM these include p53, CHK2, NBS1 and BRCA1. Targets for ATR include p53 and CHK1. One important effect of these phosphorylation events is the control of cell-cycle checkpoints (but see the figure for other essential effects). Depending on the nature of the DNA lesion, both ATM and ATR can induce the G1/S, G2/M and S-phase checkpoints. By doing so, they ensure that the cell accurately repairs the DNA damage before DNA replication or cell division occurs. How do ATM and ATR detect DNA damage? ATM and ATR can be activated in response to one or a handful of DNA lesions in the cell but how is this sensitivity achieved? In the case of ATR (and its S. cerevisiae and S. pombe orthologues, Mec1p and SpRad3, respectively), the ability to phosphorylate downstream substrates requires an associated protein (ATRIP for ATR; Lcd1p and SpRad26 for S. cerevisiae and S. pombe, respectively). The search is now on for a similar subunit for ATM. Meanwhile, a paper by Bakkenist and Kastan provides intriguing insights into early events in ATM activation as shown in the figure. Can we live without ATM and ATR? Yes and no. In ataxia-telangiectasia, the lack of a functional copy of ATM is associated with progressive neurodegeneration, immunodeficiency, predisposition to malignancy and radiation sensitivity. People who are heterozygous for ATM mutations have a slightly increased incidence of cancer. No human disease has yet been associated with total loss of ATR and mice engineered to lack ATR expression die as embryos. However, partial loss of ATR activity has recently been associated with the human autosomal recessive disorder Seckel syndrome.