ATM and the DNA damage response

Abstract

The 2005 International Workshop on Ataxia‐Telangiectasia, ATM and the DNA Damage Response took place between 8 and 11 June 2005 on the banks of Lake Maggiore, Italy. The workshop was organized by L. Chessa and D. Delia. ![][1] This workshop on ataxia‐telangiectasia marked the tenth anniversary of the discovery of the gene that is defective in this syndrome—that is, ataxia‐telangiectasia mutated ( ATM ; Savitsky et al , 1995). At the meeting, several important developments were reported, including: an expansion of the substrate repertoire of the ATM kinase; the use of animal models to analyse the signalling pathways controlled by ATM and the functional consequences of disrupting these pathways; new insights into cell‐cycle control and the maintenance of genome stability; the influence of modifier genes on ATM function; and approaches for correcting the progressive neurodegeneration that is a part of this syndrome. Ataxia‐telangiectasia is an autosomal recessive disorder characterized by neurodegeneration, immunodeficiency, hypogonadism and susceptibility to cancer. At the cellular level, it is marked by genomic instability, which is due to a defective response to double‐stranded breaks (DSBs) in DNA. This is manifested by hypersensitivity to ionizing radiation (IR) and radiomimetic compounds, and by a decreased ability to activate the DNA‐damage‐response network, which includes the cell‐cycle checkpoints (Lavin & Shiloh, 1997; Chun & Gatti, 2004). The protein product of the ATM gene is present in the nucleus as an inactive dimer or oligomer, and is activated in response to DSBs in a process that involves autophosphorylation on serine (Ser) 1,981. This causes a dissociation of the dimer to form active monomeric forms, which are able to initiate the phosphorylation of many intermediates, such as p53 and the checkpoint kinase Chk2, which are involved in DNA repair and cell‐cycle control (Bakkenist & Kastan, 2003). However, ATM is not solely responsible for initiating this … [1]: /embed/graphic-1.gif