ATM, a central controller of cellular responses to DNA damage

Abstract

Mutations in the ATM gene lead to the genetic disorder ataxiatelangiectasia. ATM encodes a protein kinase that is mainly distributed in the nucleus of proliferating cells. Recent studies reveal that ATM regulates multiple cell cycle checkpoints by phosphorylating different targets at different stages of the cell cycle. ATM also functions in the regulation of DNA repair and apoptosis, suggesting that it is a central regulator of responses to DNA double-strand breaks. Cell Death and Differentiation (2001) 8, 1052 ± 1065.

Radiation-induced DNA damage and delayed induced genomic instability

“…Recent studies have shown that DNA double-strand breaks are recognized by ATM, and activated ATM mediates phosphorylation of various nuclear proteins, including p53, CHK2/Cds1, BRCA1, NBS1, and histone H2AX (Jackson, 2002;Zhou and Elledge, 2000;Khanna et al, 2001;Shiloh and Kastan, 2001;Shiloh, 2003 Figure 2 Induction of PUCR by ionizing radiation. Radiationinduced DNA double-strand breaks give rise to altered chromatin structure within the nucleus, through the process of DNA repair which is called PUCR.…”

Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers

“…This disease is associated with an elevated risk of malignancy, primarily leukaemias and lymphomas, and a high radiosensitivity. The gene defective in this syndrome, ATM (AT mutated), encodes a nuclear 350 kDa phosphoprotein containing a carboxy terminus phosphatidylinositol 3 0 -kinase (PI-3 0 kinase) catalytic domain shared by members of a superfamily of large eukaryotic proteins involved in intracellular signalling, DNA damage-induced cell cycle checkpoints, DNA repair and recombination (reviewed in Khanna et al, 2001). After exposure of cells to ionising radiation (IR) or radiomimetic drugs, ATM's kinase activity increases several-fold, although the protein level remains unchanged.…”

HSV-1 amplicon vector-mediated expression of ATM cDNA and correction of the ataxia–telangiectasia cellular phenotype

“…The complexity of A-T is reflected in the cellular phenotype including reduced cell lifespan in culture, chromosomal instability, hypersensitivity to IR and radiomimetic agents, defective radiation-induced checkpoints at the G 1 , S and G 2 phases of the cell cycle, and defects in several signal transduction pathways. 4,5 The responsible gene, ATM (ataxia-telangiectasia mutated), was cloned in 1995 and occupies 150 kb of genomic DNA coding for a 13 kb mRNA with an open reading frame of 9.165 kb. 6 ATM is a 370 kD protein with a carboxy-terminal domain homologous to the catalytic subunits of phosphatidylinositol 3-kinases (PI-3Ks).…”