Differential effect of the overexpression of Rad2/XPG family endonucleases on genome integrity in yeast and human cells

Jimeno, Sonia; Herrera-Moyano, Emilia; Ortega, Pedro José Barrero; Aguilera, Andrés

doi:10.1016/j.dnarep.2017.06.030

Cited by 7 publications

(7 citation statements)

References 52 publications

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“…If left unrepaired, these nicks would form DSBs during the next round of replication, explaining the observed dependence on HR of RAD27 overexpressing cells. This is consistent with a recent study by Aguilera and colleagues that demonstrated an increase in recombination frequency and Rad52 foci formation when RAD27 is overexpressed ( 64 ). However, where we observed severe growth inhibition in rad52Δ mutants when overexpressing RAD27 , Aguilera and colleagues reported no such growth defect.…”

Section: Discussionsupporting

confidence: 93%

“…We interpret the presence of DNA damage markers, the activation of Rad53 as well as the accumulation of TLS-independent mutations as clear indicators of genome instability. This is consistent with a previous report by Aguilera and colleagues, however, the authors did not attempt to uncover the underlying mechanisms ( 64 ), which was the focus of our study. Overexpression of FEN1 has been observed in cancers derived from a variety of tissue types at levels approaching 50-fold greater than matched normal tissues in some cases ( 16 ).…”

Section: Discussionsupporting

confidence: 93%

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Flap endonuclease overexpression drives genome instability and DNA damage hypersensitivity in a PCNA-dependent manner

Becker

Gallo

Leung

et al. 2018

Nucleic Acids Research

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Overexpression of the flap endonuclease FEN1 has been observed in a variety of cancer types and is a marker for poor prognosis. To better understand the cellular consequences of FEN1 overexpression we utilized a model of its Saccharomyces cerevisiae homolog, RAD27. In this system, we discovered that flap endonuclease overexpression impedes replication fork progression and leads to an accumulation of cells in mid-S phase. This was accompanied by increased phosphorylation of the checkpoint kinase Rad53 and histone H2A-S129. RAD27 overexpressing cells were hypersensitive to treatment with DNA damaging agents, and defective in ubiquitinating the replication clamp proliferating cell nuclear antigen (PCNA) at lysine 164. These effects were reversed when the interaction between overexpressed Rad27 and PCNA was ablated, suggesting that the observed phenotypes were linked to problems in DNA replication. RAD27 overexpressing cells also exhibited an unexpected dependence on the SUMO ligases SIZ1 and MMS21 for viability. Importantly, we found that overexpression of FEN1 in human cells also led to phosphorylation of CHK1, CHK2, RPA32 and histone H2AX, all markers of genome instability. Our data indicate that flap endonuclease overexpression is a driver of genome instability in yeast and human cells that impairs DNA replication in a manner dependent on its interaction with PCNA.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Flap endonuclease overexpression drives genome instability and DNA damage hypersensitivity in a PCNA-dependent manner

Becker

Gallo

Leung

et al. 2018

Nucleic Acids Research

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“…Another endonuclease, FEN1, involved in Okazaki fragments processing during replication and in Base Excision Repair, also prevents 53BP1 NBs through its nucleolytic activity [ 120 ]. Besides, cells overexpressing FEN1 or XPG, an endonuclease involved in Nucleotide Excision Repair, accumulate 53BP1 NBs [ 121 ], confirming that endonucleases must be tightly regulated to avoid 53BP1 NBs due to uncontrolled DNA stand breaks. Finally, deficiency in SPARTAN, protease involved in replication-coupled DNA-protein crosslink repair [ 122 ], results in 53BP1 NBs increase [ 123 ].…”

Section: Major Cellular Processes and 53bp1 Nbsmentioning

confidence: 99%

Around and beyond 53BP1 Nuclear Bodies

Fernandez-Vidal

Vignard

Mirey

2017

IJMS

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Within the nucleus, sub-nuclear domains define territories where specific functions occur. Nuclear bodies (NBs) are dynamic structures that concentrate nuclear factors and that can be observed microscopically. Recently, NBs containing the p53 binding protein 1 (53BP1), a key component of the DNA damage response, were defined. Interestingly, 53BP1 NBs are visualized during G1 phase, in daughter cells, while DNA damage was generated in mother cells and not properly processed. Unlike most NBs involved in transcriptional processes, replication has proven to be key for 53BP1 NBs, with replication stress leading to the formation of these large chromatin domains in daughter cells. In this review, we expose the composition and organization of 53BP1 NBs and focus on recent findings regarding their regulation and dynamics. We then concentrate on the importance of the replication stress, examine the relation of 53BP1 NBs with DNA damage and discuss their dysfunction.

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“…The Rad2 family of proteins are a large group of structure-specific nucleases that function in response to aberrant nucleic acid structures [ 9 ]. As a family of evolutionarily conserved proteins, the nucleases have different names in different organisms, such as Rad2 in Saccharomyces cerevisiae [ 10 ], and flap endonuclease 1 (FEN1) and XPG in humans [ 11 ]. During DNA metabolism, these nucleases are required to repair DNA damage caused during replication or recombination, to maintain genome stability [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

ADRV 12L: A Ranaviral Putative Rad2 Family Protein Involved in DNA Recombination and Repair

Fei

Zhang

2022

Viruses

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The Andrias davidianus ranavirus (ADRV) is a member of the family Iridoviridae and belongs to the nucleocytoplasmic large DNA viruses. Based on genomic analysis, an ADRV-encoding protein, ADRV 12L, and its homologs from other iridoviruses were predicted as Rad2 family proteins based on the conserved amino acids, domains, and secondary structures. Expression analysis showed that the transcription of ADRV 12L started at 4 h post infection, and its expression was not inhibited by a DNA-replication inhibitor. Meanwhile, immunofluorescence localization showed that ADRV 12L mainly localized in viral factories and colocalized with the viral nascent DNA, which hinted at a possible role in DNA replication. Furthermore, a mutant ADRV lacking 12L (ADRV-Δ12L) was constructed. In both luciferase assays based on homologous recombination (HR) and double-strand break repair (DSBR) that followed, ADRV-Δ12L induced less luciferase activity than the wild-type ADRV, indicating that HR and DSBR were impaired in ADRV-Δ12L infected cells. In addition, infection with ADRV-Δ12L resulted in smaller plaque sizes and lower viral titers than that with wild-type ADRV, indicating an important role for 12L in efficient virus infection. Therefore, the results suggest that Rad2 homologs encoded by iridovirus have important roles in HR- and DSBR-process of the viral DNA and, thus, affect virus replication and the production of progeny virions.

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Differential effect of the overexpression of Rad2/XPG family endonucleases on genome integrity in yeast and human cells

Cited by 7 publications

References 52 publications

Flap endonuclease overexpression drives genome instability and DNA damage hypersensitivity in a PCNA-dependent manner

Flap endonuclease overexpression drives genome instability and DNA damage hypersensitivity in a PCNA-dependent manner

Around and beyond 53BP1 Nuclear Bodies

ADRV 12L: A Ranaviral Putative Rad2 Family Protein Involved in DNA Recombination and Repair

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