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J Biol Chem. 2019 Oct 22. pii: jbc.RA119.011077. doi: 10.1074/jbc.RA119.011077. [Epub ahead of print]

The telomere-binding protein Rif2 and ATP-bound Rad50 have opposing roles in the activation of yeast Tel1ATM kinase.

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Biochemistry and Molecular Biophysics, Washington University in Sait Louis School of Medicine, United States.
Washington Univ. School of Medicine, United States.
Biochemistry and Molecular Biophysics, Washington University School of Medicine, United States.
Sloan-Kettering Institute, United States.
Dept. of Molecular Biology, Sloan-Kettering Institute, United States.
Dept. Biochemistry & Molec. Biophysics, Washington Univ. School of Medicine, United States.


Saccharomyces cerevisiae Tel1 is the ortholog of human ATM kinase and initiates a cell cycle checkpoint in response to dsDNA breaks (DSBs). Tel1ATM kinase is activated synergistically by naked dsDNA and the Mre11-Rad50-Xrs2NBS1 complex (MRX). A multi-subunit protein complex, which is related to human shelterin, protects telomeres from being recognized as DSBs, thereby preventing a Tel1ATM checkpoint response. However, at very short telomeres, Tel1ATM can be recruited and activated by the MRX complex, resulting in telomere elongation. Conversely, at long telomeres, Rap1-interacting-factor 2 (Rif2) is instrumental in suppressing Tel1 activity. Here, using an in vitro reconstituted Tel1 kinase activation assay, we show that Rif2 inhibits MRX-dependent Tel1 kinase activity. Rif2 discharges the ATP-bound form of Rad50, which is essential for all MRX-dependent activities. This conclusion is further strengthened by experiments with a Rad50 allosteric ATPase mutant that maps outside of the conserved ATP binding pocket. We propose a model in which Rif2 attenuates Tel1 activity at telomeres by acting directly on Rad50 and discharging its activated ATP-bound state, thereby rendering the MRX complex incompetent for Tel1 activation. These findings expand our understanding of the mechanism by which Rif2 controls telomere length.


ATPase; DNA damage response; MRX; Rad50 ATPase; Rif2; Telomere control; ataxia telangiectasia; checkpoint control; double-stranded break; telomere

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