Abstract
The mammalian protein kinase ataxia telangiectasia mutated (ATM) is a key regulator of the DNA double-strand-break response and belongs to the evolutionary conserved phosphatidylinositol-3-kinase-related protein kinases. ATM deficiency causes ataxia telangiectasia (AT), a genetic disorder that is characterized by premature aging, cerebellar neuropathy, immunodeficiency, and predisposition to cancer. AT cells show defects in the DNA damage-response pathway, cell-cycle control, and telomere maintenance and length regulation. Likewise, in Saccharomyces cerevisiae, haploid strains defective in the TEL1 gene, the ATM ortholog, show chromosomal aberrations and short telomeres. In this review, we outline the complex role of ATM/Tel1 in maintaining genomic stability through its control of numerous aspects of cellular survival. In particular, we describe how ATM/Tel1 participates in the signal transduction pathways elicited by DNA damage and in telomere homeostasis and its importance as a barrier to cancer development.
Highlights
Ataxia telangiectasia mutated (ATM) is a protein kinase member of the evolutionary conserved phosphatidylinositol3-kinase- (PI3 K-) related kinase (PIKK) family [1, 2]
After DNA double-strand breaks (DSBs), ATM/Tel1 and ATR/Mec1, which are categorized as DNA-damage checkpoints, become active and start the signal transduction pathways that block the cell cycle and repair the DNA damage or eventually activate the cell death program
In both human cells and S. cerevisiae, ATM/Tel1 is recruited at blunt or minimally resected DNA ends by the MRN/MRX complex [37, 40]; cells that experience DNA damage in G1 are prevented from entering S-phase by the G1/S checkpoint signalling cascade that is dependent on the activity of ATM [41]
Summary
Ataxia telangiectasia mutated (ATM) is a protein kinase member of the evolutionary conserved phosphatidylinositol3-kinase- (PI3 K-) related kinase (PIKK) family [1, 2]. In particular ATM is activated by DSBs, while ATR is activated at single-strand regions of DNA via a process that involves ATRIP, RPA, and the presence of long stretch of ssDNA In both human cells and S. cerevisiae, ATM/Tel is recruited at blunt or minimally resected DNA ends by the MRN/MRX complex [37, 40]; cells that experience DNA damage in G1 are prevented from entering S-phase by the G1/S checkpoint signalling cascade that is dependent on the activity of ATM [41]. These data suggest a unified model of ATM/Tel activation where the MRN/MRX complex is the sensor of DSBs and initiates processing of the broken ends, which in turn regulates the recruitment of the ATM/Tel checkpoint kinase through binding with the NBS1/Xrs subunit, which leads to activation of the specific downstream targets [48, 92, 93]
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