title: Coordination of DNA damage tolerance mechanisms with cell cycle progression in fission yeast.
abstract: DNA damage tolerance (DDT) mechanisms allow cells to synthesize a new DNA strand when the template is damaged. Many mutations resulting from DNA damage in eukaryotes are generated during DDT when cells use the mutagenic translesion polymerases, Rev1 and Polζ, rather than mechanisms with higher fidelity. The coordination among DDT mechanisms is not well understood. We used live-cell imaging to study the function of DDT mechanisms throughout the cell cycle of the fission yeast Schizosaccharomyces pombe. We report that checkpoint-dependent mitotic delay provides a cellular mechanism to ensure the completion of high fidelity DDT, largely by homology-directed repair (HDR). DDT by mutagenic polymerases is suppressed during the checkpoint delay by a mechanism dependent on Rad51 recombinase. When cells pass the G2/M checkpoint and can no longer delay mitosis, they completely lose the capacity for HDR and simultaneously exhibit a requirement for Rev1 and Polζ. Thus, DDT is coordinated with the checkpoint response so that the activity of mutagenic polymerases is confined to a vulnerable period of the cell cycle when checkpoint delay and HDR are not possible.
authors.affiliation: a Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center , New York , NY , USA.
authors.forename: A John
authors.initials: AJ
authors.lastname: Callegari
authors.affiliation: a Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center , New York , NY , USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kelly
mesh_terms: D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004271:DNA, Fungal / Q000235:genetics* / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal; D008938:Mitosis; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000235:genetics* / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D059008:Time-Lapse Imaging
chemical_list: D004271:DNA, Fungal; C084232:RHP51 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; C425929:DNA polymerase zeta; D009713:Nucleotidyltransferases; D051135:Rad51 Recombinase; D004259:DNA-Directed DNA Polymerase
keywords: Chk1; DNA damage checkpoint; DNA damage tolerance; Polζ; Polη; Rev1; homology-directed repair; post-replication repair; ubiquitin ligase Rad5