Activation of Tel1 ATM kinase requires Rad50 ATPase and long nucleosome-free DNA but no DNA ends

In , Tel1 protein kinase, the ortholog of human ataxia telangiectasia-mutated (ATM), is activated in response to DNA double-strand breaks. Biochemical studies with human ATM and genetic studies in yeast suggest that recruitment and activation of Tel1 depends on the heterotrimeric MRX complex, compos...

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Bibliographic Details
Published in:The Journal of biological chemistry 2019-06, Vol.294 (26), p.10120
Main Authors: Hailemariam, Sarem, Kumar, Sandeep, Burgers, Peter M
Format: Article
Language:English
Subjects:
DNA Breaks, Double-Stranded
DNA, Fungal - genetics
DNA, Fungal - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Endodeoxyribonucleases - genetics
Endodeoxyribonucleases - metabolism
Exodeoxyribonucleases - genetics
Exodeoxyribonucleases - metabolism
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Nucleosomes
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - growth & development
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - genetics
Saccharomyces cerevisiae Proteins - metabolism
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Summary:In , Tel1 protein kinase, the ortholog of human ataxia telangiectasia-mutated (ATM), is activated in response to DNA double-strand breaks. Biochemical studies with human ATM and genetic studies in yeast suggest that recruitment and activation of Tel1 depends on the heterotrimeric MRX complex, composed of Mre11, Rad50, and Xrs2 (human Nbs1). However, the mechanism of activation of Tel1 by MRX remains unclear, as does the role of effector DNA. Here we demonstrate that dsDNA and MRX activate Tel1 synergistically. Although minimal activation was observed with 80-mer duplex DNA, the optimal effector for Tel1 activation is long, nucleosome-free DNA. However, there is no requirement for DNA double-stranded termini. The ATPase activity of Rad50 is critical for activation. In addition to DNA and Rad50, either Mre11 or Xrs2, but not both, is also required. Each of the three MRX subunits shows a physical association with Tel1. Our study provides a model of how the individual subunits of MRX and DNA regulate Tel1 kinase activity.
ISSN:1083-351X