Stress Activated Protein Kinase Pathway Modulates Homologous Recombination in Fission Yeast

Bellini, Angela; Girard, Pierre‐Marie; Lambert, Sarah; Tessier, Ludovic; Sage, Évelyne; Francesconi, Stefania

doi:10.1371/journal.pone.0047987

Cited by 6 publications

(15 citation statements)

References 59 publications

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“…Alternatively, endogenous ROS may activate the stress-activated protein kinase (SAPK) pathway. Recently, the SAPK-dependent phosphorylation of Rad52 was shown to be indispensable for the regulation of HR in fission yeast [42]. Therefore, modulation of SAPK or other ROS-responsive enzymes is likely to affect the mammalian HR pathway.…”

Section: Discussionmentioning

confidence: 99%

Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses

Kobayashi

Saito

Okui

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Ataxia telangiectasia (AT) is caused by a mutation in the ataxia-telangiectasia-mutated (ATM) gene; the condition is associated with hyper-radiosensitivity, abnormal cell-cycle checkpoints, and genomic instability. AT patients also show cerebellar ataxia, possibly due to reactive oxygen species (ROS) sensitivity in neural cells. The ATM protein is a key regulator of the DNA damage response. Recently, several AT-like disorders have been reported. The genes responsible for them are predicted to encode proteins that interact with ATM in the DNA-damage response. Ataxia with oculomotor apraxia types 1-3 (AOA1, 2, and 3) result in a neurodegenerative and cellular phenotype similar to AT; however, the basis of this phenotypic similarity is unclear. Here, we show that the cells of AOA3 patients display aberrant ATM-dependent phosphorylation and apoptosis following γ-irradiation. The ATM-dependent response to H2O2 treatment was abrogated in AOA3 cells. Furthermore, AOA3 cells had reduced ATM activity. Our results suggest that the attenuated ATM-related response is caused by an increase in endogenous ROS in AOA3 cells. Pretreatment of cells with pyocyanin, which induces endogenous ROS production, abolished the ATM-dependent response. Moreover, AOA3 cells had decreased homologous recombination (HR) activity, and pyocyanin pretreatment reduced HR activity in HeLa cells. These results indicate that excess endogenous ROS represses the ATM-dependent cellular response and HR repair in AOA3 cells. Since the ATM-dependent cell-cycle checkpoint is an important block to carcinogenesis, such inactivation of ATM may lead to tumorigenesis as well as neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses

Kobayashi

Saito

Okui

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…In S. cerevisiae, the biological role of Rad52 phosphorylation remains to be determined. In S. pombe Rad52 phosporylation was induced under conditions of oxidative stress or in cells deficient in Rad51 or Mus81 [ 111 , 112 ]. Similar, in humans RAD52 is phosphorylated in response to DNA damage at Tyr104 by c-ABL tyrosine kinase in an ATM and DNA-PKcs dependent manner [ 113 ].…”

Section: Regulation Of Rad52 In the Cellmentioning

confidence: 99%

Reappearance from Obscurity: Mammalian Rad52 in Homologous Recombination

Hanamshet

Mazina

Mazin

2016

Genes

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Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans. In yeast, Rad52 is important for most HR events; Rad52 mutations disrupt repair of DNA double-strand breaks and targeted DNA integration. Surprisingly, in mammals, Rad52 knockouts showed no significant DNA repair or recombination phenotype. However, recent work demonstrated that mutations in human RAD52 are synthetically lethal with mutations in several other HR proteins including BRCA1 and BRCA2. These new findings indicate an important backup role for Rad52, which complements the main HR mechanism in mammals. In this review, we focus on the Rad52 activities and functions in HR and the possibility of using human RAD52 as therapeutic target in BRCA1 and BRCA2-deficient familial breast cancer and ovarian cancer.

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“…Thus, rad52YFP and rad52-S365G-YFP cells were exposed to UVA or H 2 O 2 after synchronization in early S phase as described in [30]. Rad52 phosphorylation was assessed by western blotting at 0 and 90 minutes after irradiation and after 90 minutes of release in medium containing H 2 O 2 .…”

Section: Resultsmentioning

confidence: 99%

Fission Yeast Rad52 Phosphorylation Restrains Error Prone Recombination Pathways

Bellini

Girard²,

Tessier³

et al. 2014

PLoS ONE

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Rad52 is a key protein in homologous recombination (HR), a DNA repair pathway dedicated to double strand breaks and recovery of blocked or collapsed replication forks. Rad52 allows Rad51 loading on single strand DNA, an event required for strand invasion and D-loop formation. In addition, Rad52 functions also in Rad51 independent pathways because of its ability to promote single strand annealing (SSA) that leads to loss of genetic material and to promote D-loops formation that are cleaved by Mus81 endonuclease. We have previously reported that fission yeast Rad52 is phosphorylated in a Sty1 dependent manner upon oxidative stress and in cells where the early step of HR is impaired because of lack of Rad51. Here we show that Rad52 is also constitutively phosphorylated in mus81 null cells and that Sty1 partially impinges on such phosphorylation. As upon oxidative stress, the Rad52 phosphorylation in rad51 and mus81 null cells appears to be independent of Tel1, Rad3 and Cdc2. Most importantly, we show that mutating serine 365 to glycine (S365G) in Rad52 leads to loss of the constitutive Rad52 phosphorylation observed in cells lacking Rad51 and to partial loss of Rad52 phosphorylation in cells lacking Mus81. Contrariwise, phosphorylation of Rad52-S365G protein is not affected upon oxidative stress. These results indicate that different Rad52 residues are phosphorylated in a Sty1 dependent manner in response to these distinct situations. Analysis of spontaneous HR at direct repeats shows that mutating serine 365 leads to an increase in spontaneous deletion-type recombinants issued from mitotic recombination that are Mus81 dependent. In addition, the recombination rate in the rad52-S365G mutant is further increased by hydroxyurea, a drug to which mutant cells are sensitive.

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Stress Activated Protein Kinase Pathway Modulates Homologous Recombination in Fission Yeast

Cited by 6 publications

References 59 publications

Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses

Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses

Reappearance from Obscurity: Mammalian Rad52 in Homologous Recombination

Fission Yeast Rad52 Phosphorylation Restrains Error Prone Recombination Pathways

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