title: Break-induced replication requires DNA damage-induced phosphorylation of Pif1 and leads to telomere lengthening.
abstract: Broken replication forks result in DNA breaks that are normally repaired via homologous recombination or break induced replication (BIR). Mild insufficiency in the replicative ligase Cdc9 in budding yeast Saccharomyces cerevisiae resulted in a population of cells with persistent DNA damage, most likely due to broken replication forks, constitutive activation of the DNA damage checkpoint and longer telomeres. This telomere lengthening required functional telomerase, the core DNA damage signaling cascade Mec1-Rad9-Rad53, and the components of the BIR repair pathway - Rad51, Rad52, Pol32, and Pif1. The Mec1-Rad53 induced phosphorylation of Pif1, previously found necessary for inhibition of telomerase at double strand breaks, was also important for the role of Pif1 in BIR and telomere elongation in cdc9-1 cells. Two other mutants with impaired DNA replication, cdc44-5 and rrm3Δ, were similar to cdc9-1: their long telomere phenotype was dependent on the Pif1 phosphorylation locus. We propose a model whereby the passage of BIR forks through telomeres promotes telomerase activity and leads to telomere lengthening.
authors.affiliation: Institute of Cell Biology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Vasianovich
authors.affiliation: Institute of Cell Biology, University of Edinburgh, Edinburgh, United Kingdom; Institut de Recherche en Immunologie et en Cancérologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Lea A
authors.initials: LA
authors.lastname: Harrington
authors.affiliation: Institute of Cell Biology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Makovets
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051818:Replication Protein C / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D059505:Telomere Homeostasis
chemical_list: C000607890:CDC9 protein, S cerevisiae; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C084903:RFC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D064447:Checkpoint Kinase 2; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C067022:RAD53 protein, S cerevisiae; D019098:Telomerase; C085463:PIF1 protein, S cerevisiae; D004265:DNA Helicases; D051818:Replication Protein C; D011088:DNA Ligases; D000072481:DNA Ligase ATP