Multifunctional role of ATM/Tel1 kinase in genome stability: from the DNA damage response to telomere maintenance

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.

Figure 1

Description of the relevant proteins recruited to DNA double-strand break. In undamaged cells, ATM is an inactive multimer. After DSBs, ATM is recruited to the site of damage by the MRN complex, triggering its autophosphorylation, monomerization, and subsequent activation. Adjacent to the site of damage, the first target of ATM is the histone H2AX, followed by the phosphorylation of MDC1 and the recruitment of the ubiquitin ligase RNF8. RNF8 binding causes H2AX ubiquitylation, facilitating the association of BRCA1 and, ultimately 53BP1, that is required for ATM retention at the site of damage.

Figure 2

Summary of the ATM signaling network. Schematic representation of ATM signaling pathways as reported in the text.

Figure 3

Telomere structure in human and S. cerevisiae. Human telomeres consist of kilobases of TTAGGG repeats, ending with a 3′ overhang, G-rich strand. The shelterin complex includes six proteins: TRF1 and TRF2, which bind directly the double-stranded telomeric DNA and are held together by TIN2, RAP1 that interacts with TRF2, POT1 that associates with telomeric ssDNA, and TPP1. These factors mediate the generation of higher-order structure at chromosome ends (T-loop) by invasion of the single-stranded G-overhang into the double-stranded TTAGGG repeats. In Budding yeast, the double-stranded telomeric sequence is bound by Rap1, which regulates telomere length together with Rif1 and Rif2. Cdc13 Ten1 and Stn1 bind to the single strand overhang. In both human and S. cerevisiae, the heterodimeric Ku complex (Ku70/80) interacts with the terminal part of the telomere, providing a protective role. The heterotrimeric complex MRX/MRN (MRE11/Mre11, RAD50/Rad50, and NBS1/Xrs2) promotes ATM/Tel1 recruitment, with a central role in telomere capping and length regulation.