End Resection Initiates Genomic Instability in the Absence of Telomerase

Abstract

Telomere dysfunction causes genomic instability. However, the mechanism that initiates this instability when telomeres become short is unclear. We measured the mutation rate and loss of heterozygosity along a chromosome arm in diploid yeast that lacked telomerase to distinguish between mechanisms for the initiation of instability. Sequence loss was localized near chromosome ends in the absence of telomerase but not after breakage of a dicentric chromosome. In the absence of telomerase, the increase in mutation rate is dependent on the exonuclease Exo1p. Thus, exonucleolytic end resection, rather than chromosome fusion and breakage, is the primary mechanism that initiates genomic instability when telomeres become short.

ACKNOWLEDGMENTS

We thank Jef Boeke, Forrest Spencer, David Feldser, Chris Frank, and Tom Cunningham for critical reading of the manuscript and Joe Lawler for useful discussions. We thank Jef Boeke, Abram Gabriel, Marc Gartenberg, and Ted Weinert for providing yeast strains and vectors. We thank David Feldser for deletion of MRE11.

This work was supported by the Predoctoral Training Program in Human Genetics and Molecular Biology and the National Science Foundation (J.A.H.) and by NIH grant GM43080 (C.W.G).