PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1

Catherine Johnson; Vamsi K. Gali; Tatsuro S. Takahashi; Takashi Kubota

doi:10.1016/j.celrep.2016.06.030

PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1

Catherine Johnson, Vamsi K. Gali, Tatsuro S. Takahashi, Takashi Kubota^* (Corresponding Author)

^*Corresponding author for this work

Medical Sciences

Osaka University

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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 ringshaped 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.

Original language	English
Pages (from-to)	684-695
Number of pages	12
Journal	Cell Reports
Volume	16
Issue number	3
Early online date	30 Jun 2016
DOIs	https://doi.org/10.1016/j.celrep.2016.06.030
Publication status	Published - 19 Jul 2016

Bibliographical note

Acknowledgments
We thank Richard Kolodner, Grant Brown, and Daniel Durocher for strains and plasmids. We thank Anne Donaldson, Alexander Lorenz, and Shin-ichiro Hiraga from University of Aberdeen for careful reading of the manuscript. Research in T.K.’s lab is supported by Medical Research Council Career Development Fellowship L019698/1. V.K.G. was supported by Biotechnology and Biological Sciences Research Council grant K006304/1. T.S.T. was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (nos. 23131507 and 25131712).

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PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Final published version, 2.93 MBLicence: CC BY

Takashi Kubota
Person: Academic, Academic Related - Research

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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 ringshaped 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.",

author = "Catherine Johnson and Gali, {Vamsi K.} and Takahashi, {Tatsuro S.} and Takashi Kubota",

note = "Acknowledgments We thank Richard Kolodner, Grant Brown, and Daniel Durocher for strains and plasmids. We thank Anne Donaldson, Alexander Lorenz, and Shin-ichiro Hiraga from University of Aberdeen for careful reading of the manuscript. Research in T.K.{\textquoteright}s lab is supported by Medical Research Council Career Development Fellowship L019698/1. V.K.G. was supported by Biotechnology and Biological Sciences Research Council grant K006304/1. T.S.T. was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (nos. 23131507 and 25131712).",

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N1 - Acknowledgments We thank Richard Kolodner, Grant Brown, and Daniel Durocher for strains and plasmids. We thank Anne Donaldson, Alexander Lorenz, and Shin-ichiro Hiraga from University of Aberdeen for careful reading of the manuscript. Research in T.K.’s lab is supported by Medical Research Council Career Development Fellowship L019698/1. V.K.G. was supported by Biotechnology and Biological Sciences Research Council grant K006304/1. T.S.T. was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (nos. 23131507 and 25131712).

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N2 - 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 ringshaped 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.

AB - 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 ringshaped 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.

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DO - 10.1016/j.celrep.2016.06.030

M3 - Article

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JO - Cell Reports

JF - Cell Reports

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PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1

Abstract

Bibliographical note

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