title: PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1.
abstract: Loss of the genome maintenance factor Elg1 causes serious genome instability that leads to cancer, but the underlying mechanism is unknown. Elg1 forms the major subunit of a replication factor C-like complex, Elg1-RLC, which unloads the ring-shaped polymerase clamp PCNA from DNA during replication. Here, we show that prolonged retention of PCNA on DNA into G2/M phase is the major cause of genome instability in elg1Δ yeast. Overexpression-induced accumulation of PCNA on DNA causes genome instability. Conversely, disassembly-prone PCNA mutants that relieve PCNA accumulation rescue the genome instability of elg1Δ cells. Covalent modifications to the retained PCNA make only a minor contribution to elg1Δ genome instability. By engineering cell-cycle-regulated ELG1 alleles, we show that abnormal accumulation of PCNA on DNA during S phase causes moderate genome instability and its retention through G2/M phase exacerbates genome instability. Our results reveal that PCNA unloading by Elg1-RLC is critical for genome maintenance.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Gali
authors.affiliation: Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Tatsuro S
authors.initials: TS
authors.lastname: Takahashi
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. Electronic address: t.kubota@abdn.ac.uk.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kubota
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D004271:DNA, Fungal / Q000235:genetics*; D016195:G2 Phase / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics*; D051818:Replication Protein C / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D004271:DNA, Fungal; C477609:Elg1 protein, S cerevisiae; D018809:Proliferating Cell Nuclear Antigen; D029701:Saccharomyces cerevisiae Proteins; D051818:Replication Protein C