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Molecular and Cellular Biology, November 2003, p. 8202-8215, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8202-8215.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Ku Heterodimer Performs Separable Activities at Double-Strand Breaks and Chromosome Termini

Alison A. Bertuch1,2* and Victoria Lundblad2

Department of Pediatrics, Hematology/Oncology Section,1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 770302

Received 14 March 2003/ Returned for modification 28 April 2003/ Accepted 7 August 2003

The Ku heterodimer functions at two kinds of DNA ends: telomeres and double-strand breaks. The role that Ku plays at these two classes of termini must be distinct, because Ku is required for accurate and efficient joining of double-strand breaks while similar DNA repair events are normally prohibited at chromosome ends. Toward defining these functional differences, we have identified eight mutations in the large subunit of the Saccharomyces cerevisiae Ku heterodimer (YKU80) which retain the ability to repair double-strand breaks but are severely impaired for chromosome end protection. Detailed characterization of these mutations, referred to as yku80tel alleles, has revealed that Ku performs functionally distinct activities at subtelomeric chromatin versus the end of the chromosome, and these activities are separable from Ku's role in telomere length regulation. While at the chromosome terminus, we propose that Ku participates in two different activities: it facilitates telomerase-mediated G-strand synthesis, thereby contributing to telomere length regulation, and it separately protects against resection of the C-strand, thereby contributing to protection of chromosome termini. Furthermore, we propose that the Ku heterodimer performs discrete sets of functions at chromosome termini and at duplex subtelomeric chromatin, via separate interactions with these two locations. Based on homology modeling with the human Ku structure, five of the yku80tel alleles mutate residues that are conserved between the yeast and human Ku80 proteins, suggesting that these mutations probe activities that are shared between yeast and humans.

* Corresponding author. Mailing address: Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone (832) 824-4579. Fax: (832) 825-4657. E-mail: abertuch{at}bcm.tmc.edu.

Molecular and Cellular Biology, November 2003, p. 8202-8215, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8202-8215.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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