ATM and ATR: sensing DNA damage

Abstract

Cellular response to genotoxic stress is a very complex process, and it usually starts with the "sensing" or "detection" of the DNA damage, followed by a series of events that include signal transduction and activation of transcription factors. The activated transcription factors induce expressions of many genes which are involved in cellular functions such as DNA repair, cell cycle arrest, and cell death. There have been extensive studies from multiple disciplines exploring the mechanisms of cellular genotoxic responses, which have resulted in the identification of many cellular components involved in this process, including the mitogen-activated protein kinases (MAPKs) cascade. Although the initial activation of protein kinase cascade is not fully understood, human protein kinases ATM (ataxia-telangiectasia, mutated) and ATR (ATM and Rad3-related) are emerging as potential sensors of DNA damage. Current progresses in ATM/ATR research and related signaling pathways are discussed in this review, in an effort to facilitate a better understanding of genotoxic stress response.

Figure 1

A general schematic representation of cellular re-sponses to genotoxic stress. Ultraviolet (UV), ionizing radia-tion (IR), and various chemicals can induce DNA damage, such as double strand breaks (DSBs), which can be detected by “sensors”. This generates some signal that can be transduced by the transducers to effector molecules. Finally, there is the presence of an attenuation mechanism to control the cellular response to genotoxic stress.

Figure 2

Regulation of p53 protein by ATM and ATR. ATM and ATR can influence the activity of p53 directly through phos-phorylation or indirectly through the action of other kinases. Furthermore, ATM can regulate p53 through phosphorylation of Mdm2 molecule, the negative regulator of p53, which can be up-regulated by p53.

Figure 3

The relationship between ATM and carcinogenesis.