Interplay between ATM and ATR in the regulation of common fragile site stability

Ozeri-Galai, Efrat; Schwartz, Michal; Rahat, Ayelet; Kerem, Batsheva

doi:10.1038/sj.onc.1210849

Cited by 54 publications

(50 citation statements)

References 45 publications

(57 reference statements)

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“…Recent studies have revealed that the presence of AT-rich sequences in the region can form highly stable secondary structures promoting DNA breakage 24,25 . Of note, the ATM pathway-involved in the regulation of fragile sites 26 -was found to be significantly downregulated in our patients harbouring FGFR2 rearrangements, suggesting this pathway may play an important role in the occurrence of these fusion events in iCCA.…”

Section: Discussionmentioning

confidence: 99%

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Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma

et al. 2015

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Intrahepatic cholangiocarcinoma (iCCA) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. By performing RNA-and exome-sequencing analyses, we report a novel fusion event, FGFR2-PPHLN1 (16%), and damaging mutations in the ARAF oncogene (11%). Here we demonstrate that the chromosomal translocation t(10;12)(q26;q12) leading to FGFR2-PPHLN1 fusion possesses transforming and oncogenic activity, which is successfully inhibited by a selective FGFR2 inhibitor in vitro. Among the ARAF mutations, N217I and G322S lead to activation of the pathway and N217I shows oncogenic potential in vitro. Screening of a cohort of 107 iCCA patients reveals that FGFR2 fusions represent the most recurrent targetable alteration (45%, 17/107), while they are rarely present in other primary liver tumours (0/100 of hepatocellular carcinoma (HCC); 1/21 of mixed iCCA-HCC). Taken together, around 70% of iCCA patients harbour at least one actionable molecular alteration (FGFR2 fusions, IDH1/2, ARAF, KRAS, BRAF and FGF19) that is amenable for therapeutic targeting.

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Section: Discussionmentioning

confidence: 99%

“…26). Interestingly, ATM pathway genes were found to be significantly downregulated in patients harbouring FGFR2 fusions as revealed by ssGSEA (Fig.…”

Section: Resultsmentioning

confidence: 99%

Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma

et al. 2015

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“…Fischer and co-workers reported similar findings in which hypoxia drives the formation of double minutes, fragile sites and anaphase bridges, which can lead to the development of gene (35) 10 (33) 26 (74) 30 (83) 12 (55) 19 (79) Intrachromosomal rearrangements* (%) 0 (0) 2 (7) 16 (46) 23 (64) 4 (18) 17 ( amplifications in glioblastoma (Fischer et al, 2008). A study by Ozeri-Galai and colleagues showed that both ATM and ATR kinases are involved in regulating the stability of fragile sites (Ozeri-Galai et al, 2008). Furthermore, they have shown that the induction of fragile sites by replication stress leads to formation of DNA-dsbs and activation of ATM, ATR and c-H2AX.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia has been documented to drive the fusion of double minutes into fragile sites, thereby generating homogenously staining regions (Coquelle et al, 1998). Fragile sites have been thought to be involved in DNAdsb-induced chromosomal aberrations (Ozeri-Galai et al, 2008). Fischer and co-workers reported similar findings in which hypoxia drives the formation of double minutes, fragile sites and anaphase bridges, which can lead to the development of gene (35) 10 (33) 26 (74) 30 (83) 12 (55) 19 (79) Intrachromosomal rearrangements* (%) 0 (0) 2 (7) 16 (46) 23 (64) 4 (18) 17 ( amplifications in glioblastoma (Fischer et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Chronic hypoxia compromises repair of DNA double-strand breaks to drive genetic instability

Kumareswaran

Ludkovski

Meng

et al. 2012

Journal of Cell Science

112

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SummaryHypoxic cells have been linked to genetic instability and tumor progression. However, little is known about the exact relationship between DNA repair and genetic instability in hypoxic cells. We therefore tested whether the sensing and repair of DNA double-strand breaks (DNA-dsbs) is altered in irradiated cells kept under continual oxic, hypoxic or anoxic conditions. Synchronized G0-G1 human fibroblasts were irradiated (0-10 Gy) after initial gassing with 0% O 2 (anoxia), 0.2% O 2 (hypoxia) or 21% O 2 (oxia) for 16 hours. The response of phosphorylated histone H2AX (c-H2AX), phosphorylated ataxia telangiectasia mutated [ATM(Ser1981)], and the p53 binding protein 1 (53BP1) was quantified by intranuclear DNA repair foci and western blotting. At 24 hours following DNA damage, residual c-H2AX, ATM(Ser1981) and 53BP1 foci were observed in hypoxic cells. This increase in residual DNA-dsbs under hypoxic conditions was confirmed using neutral comet assays. Clonogenic survival was also reduced in chronically hypoxic cells, which is consistent with the observation of elevated G1-associated residual DNA-dsbs. We also observed an increase in the frequency of chromosomal aberrations in chronically hypoxic cells. We conclude that DNA repair under continued hypoxia leads to decreased repair of G1-associated DNA-dsbs, resulting in increased chromosomal instability. Our findings suggest that aberrant DNA-dsb repair under hypoxia is a potential factor in hypoxia-mediated genetic instability.Key words: DNA double-strand breaks, hypoxia, non-homologous end joining, DNA double-strand break sensors, c-H2AX, genetic instability Introduction Human cells have evolved specific pathways to repair DNA double-strand breaks (DNA-dsbs) and enact cell cycle checkpoints following DNA damage to ensure genetic stability. These pathways could be oxygen sensitive because endogenous and exogenous DNA damage can be differentially processed and repaired in oxic versus hypoxic cells Bristow and Hill, 2008). For example, intratumoral hypoxia can drive genetic instability and accelerate tumor progression. It can also lead to altered radio-or chemoresistance, enhanced mutagenesis, impaired DNA repair and increased systemic metastasis (reviewed by Bindra et al., 2007;Bristow and Hill, 2008;Huang et al., 2007). The consequence of hypoxic exposure on DNA damage response (DDR) sensing and signalling might relate, in part, to the oxygen level (e.g. hypoxia or anoxia) and the duration of the hypoxic exposure (acute or cycling hypoxia versus chronic or prolonged hypoxia).One of the most lethal DNA lesions is a DNA-dsb. Incorrectly or non-repaired DNA-dsbs could result in chromosomal deletions, amplifications, aneuploidy and genetic instability (Helleday et al., 2007). Despite the fact that the vast majority of human tumors contain hypoxic sub-regions, little is known about the potential effects of continual hypoxia on DNA-dsb sensing and processing. The signal transduction processes in response to DNA-dsbs are dependent on the kinase activity and autophos...

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“…Recently, several articles have reported that activated ERK regulates ATR activity (27,28,30). Although these findings are 1 Unpublished data.…”

Section: Cox-2 Induces Erk Activationmentioning

confidence: 63%

Cyclooxygenase-2 Up-Regulates Ataxia Telangiectasia and Rad3 Related through Extracellular Signal-Regulated Kinase Activation

Kim

Lee

Park

et al. 2009

Molecular Cancer Research

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Cyclooxygenase-2 (COX-2) overexpression caused prolonged G 2 arrest after exposure to ionizing radiation (IR) in our previous study. We were therefore interested in investigating the function of COX-2 in the G 2 checkpoint pathway. Interestingly, we found that cells in which COX-2 is overexpressed showed up-regulated ataxia telangiectasia and Rad3 related (ATR) expression compared with control cells. In this study, we investigated the mechanism of ATR up-regulation by COX-2 and tested our hypothesis that COX-2-induced extracellular signal-regulated kinase (ERK) activation mediates up-regulation of ATR by COX-2. To investigate the relationship between COX-2 and ATR, we used two stable COX-2-overexpressing cancer cell lines (HCT116-COX-2 and H460-COX-2), a COX-2 knockdown A549 lung cancer cell line (AS), and an ATR knockdown HCT116 cell line. Cells were treated with various drugs [celecoxib, prostaglandin E 2 (PGE 2 ), PD98059, U0126, and hydroxyurea] and were then analyzed using reverse transcription-PCR, confocal microscopy, Western blotting, and clonogenic assay. COX-2-overexpressing cells were shown to have increased ERK phosphorylation and ATR expression compared with control cells, whereas AS cells were shown to have decreased levels of phospho-ERK and ATR. In addition, exogenously administered PGE 2 increased ERK phosphorylation. Inhibition of ERK phosphorylation decreased ATR expression in both HCT116-COX-2 and A549 cells. HCT116-COX-2 cells were resistant to IR or hydroxyurea compared with HCT116-Mock cells, whereas administration of ATR shRNA showed the opposite effect. COX-2 stimulates ERK phosphorylation via PGE 2 . This COX-2-induced ERK activation seems to increase ATR expression and activity in endogenous COX-2-overexpressing cancer cells as well as in COX-2-overexpressing stable cell

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Interplay between ATM and ATR in the regulation of common fragile site stability

Cited by 54 publications

References 45 publications

Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma

Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma

Chronic hypoxia compromises repair of DNA double-strand breaks to drive genetic instability

Cyclooxygenase-2 Up-Regulates Ataxia Telangiectasia and Rad3 Related through Extracellular Signal-Regulated Kinase Activation

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