title: Ontogeny of Unstable Chromosomes Generated by Telomere Error in Budding Yeast.
abstract: DNA replication errors at certain sites in the genome initiate chromosome instability that ultimately leads to stable genomic rearrangements. Where instability begins is often unclear. And, early instability may form unstable chromosome intermediates whose transient nature also hinders mechanistic understanding. We report here a budding yeast model that reveals the genetic ontogeny of genome rearrangements, from initial replication error to unstable chromosome formation to their resolution. Remarkably, the initial error often arises in or near the telomere, and frequently forms unstable chromosomes. Early unstable chromosomes may then resolve to an internal "collection site" where a dicentric forms and resolves to an isochromosome (other outcomes are possible at each step). The initial telomere-proximal unstable chromosome is increased in mutants in telomerase subunits, Tel1, and even Rad9, with no known telomere-specific function. Defects in Tel1 and in Rrm3, a checkpoint protein kinase with a role in telomere maintenance and a DNA helicase, respectively, synergize dramatically to generate unstable chromosomes, further illustrating the consequence of replication error in the telomere. Collectively, our results suggest telomeric replication errors may be a common cause of seemingly unrelated genomic rearrangements located hundreds of kilobases away.
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Tracey
authors.identifier: http://orcid.org/0000-0001-9758-2657
authors.initials: T
authors.lastname: Beyer
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Ted
authors.initials: T
authors.lastname: Weinert
mesh_terms: D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics*; D015825:Chromosomes, Fungal / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D059765:Homologous Recombination / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics*; D019098:Telomerase / Q000737:chemistry / Q000235:genetics; D016615:Telomere / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; C069930:rad9 protein; D017346:Protein Serine-Threonine Kinases; C513623:TEL1 protein, S cerevisiae; D019098:Telomerase; C459081:Rrm3 protein, S cerevisiae; D004265:DNA Helicases