Activation of Tel1ATM kinase requires Rad50 ATPase and long nucleosome-free DNA but no DNA ends

Sarem Hailemariam, Sandeep Kumar, Peter M. Burgers

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

In Saccharomyces cerevisiae, 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 Tel1ATM depends on the hetero-trimeric MRXMRN 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.

Original languageEnglish
Pages (from-to)10120-10130
Number of pages11
JournalJournal of Biological Chemistry
Volume294
Issue number26
DOIs
StatePublished - Jun 28 2019

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