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

Research output: Contribution to journalArticle

19 Citations (Scopus)
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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 languageEnglish
Pages (from-to)684-695
Number of pages12
JournalCell Reports
Volume16
Issue number3
Early online date30 Jun 2016
DOIs
Publication statusPublished - 19 Jul 2016

Fingerprint

Genomic Instability
G2 Phase
Proliferating Cell Nuclear Antigen
Cell Division
Genes
DNA
Genome
Replication Protein C
Cell engineering
Maintenance
Clamping devices
Unloading
DNA Replication
S Phase
Yeast
Cell Cycle
Yeasts
Alleles
Neoplasms

Cite this

PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1. / Johnson, Catherine; Gali, Vamsi K.; Takahashi, Tatsuro S.; Kubota, Takashi.

In: Cell Reports, Vol. 16, No. 3, 19.07.2016, p. 684-695.

Research output: Contribution to journalArticle

Johnson, Catherine ; Gali, Vamsi K. ; Takahashi, Tatsuro S. ; Kubota, Takashi. / PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1. In: Cell Reports. 2016 ; Vol. 16, No. 3. pp. 684-695.
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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.",
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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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