MCB Accepts, published online ahead of print on 14 July 2008

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Mol. Cell. Biol. doi:10.1128/MCB.00326-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A novel Tel1/ATM N-terminal motif, TAN, is essential for telomere length maintenance and a DNA damage response

Jeffrey J. Seidel, Carol M. Anderson, and Elizabeth H. Blackburn^*

Department of Biochemistry and Biophysics, 600 16^th Street, Rm S316, University of California, San Francisco, San Francisco, CA 94158

^* To whom correspondence should be addressed. Email: Elizabeth.Blackburn{at}ucsf.edu.

Tel1/ATM, a conserved phosphatidylinositol-3 kinase (PI3K) related kinase (PIKK), acts in the response to DNA damage and regulates telomere maintenance. PIKK family members share an extended N-terminal region of low sequence homology. Sequence alignment of the N-terminus of Tel1/ATM orthologs revealed a conserved, novel motif we term TAN (Tel1/ATM N-terminal motif). Point mutations in conserved residues of the TAN resulted in telomere shortening, and its deletion caused the same short telomere phenotype as complete deletion of Tel1. Overexpressing Tel1 TAN mutants did not rescue telomere shortening. The TAN motif was also essential for the function of Tel1 in the response to DNA damage, as TAN-deleted Tel1 was indistinguishable from the complete lack of Tel1 in causing reduced viability and signaling through Rad53 upon DNA damage. Strikingly, TAN deletion reduced recruitment of Tel1 to a double strand DNA break. Together, these results define a conserved sequence motif within an otherwise poorly defined region of the Tel1/ATM kinase family proteins that is essential for normal Tel1 function.