Reduced Levels of DNA Polymerase δ Induce Chromosome Fragile Site Instability in Yeast

Abstract

Specific regions of genomes (fragile sites) are hot spots for the chromosome rearrangements that are associated with many types of cancer cells. Understanding the molecular mechanisms regulating the stability of chromosome fragile sites, therefore, has important implications in cancer biology. We previously identified two chromosome fragile sites in Saccharomyces cerevisiae that were induced in response to the reduced expression of Pol1p, the catalytic subunit of DNA polymerase α. In the study presented here, we show that reduced levels of Pol3p, the catalytic subunit of DNA polymerase δ, induce instability at these same sites and lead to the generation of a variety of chromosomal aberrations. These findings demonstrate that a change in the stoichiometry of replicative DNA polymerases results in recombinogenic DNA lesions, presumably double-strand DNA breaks.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank Malgorzata Gawel for assistance with the Southern blots and CGH microarray analysis; Jennifer Gerton, Phoebe Lee, and Jeremy DeMai for strain constructions; and all members of the Petes lab for useful discussions. We also thank Abram Gabriel for sharing unpublished information.

The research was supported by an NIH grant to T.D.P. (GM52319) and a grant from the Leukemia and Lymphoma Society to F.J.L. (3427-07).