Hypoxia-Induced Phosphorylation of Chk2 in an Ataxia Telangiectasia Mutated–Dependent Manner

Gibson, Shannon L.; Bindra, Ranjit S.; Glazer, Peter M.

doi:10.1158/0008-5472.can-05-1160

Cited by 81 publications

(74 citation statements)

References 33 publications

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“…It is also likely that, like Chk2, Chk1 contributes to the reoxygenation-induced cell cycle arrest. 30,45 Taken together these data indicate that Chk1 functions during both hypoxia and reoxygenation. We have carried out a modified form of our colony survival experiment to determine in which phase, hypoxia or reoxygenation, the cells are more sensitive (Fig.…”

Section: Chk1 Signalling In Hypoxia/reoxygenationmentioning

confidence: 61%

Exposure to acute hypoxia induces a transient DNA damage response which includes Chk1 and TLK1

Pires¹,

Bencokova²,

McGurk³

et al. 2010

Cell Cycle

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Severe hypoxia has been demonstrated to induce a replication arrest which is associated with decreased levels of nucleotides. Chk1 is rapidly phosphorylated in response to severe hypoxia and in turn deactivates TLK1 through phosphorylation. Loss of Chk1 has been shown to sensitize cells to hypoxia/reoxygenation. After short (acute) exposure to hypoxia this is due to an increased rate of reoxygenation-induced replication restart and subsequent p53-dependent apoptosis. After longer (chronic) exposure to hypoxia S phase cells do not undergo reoxygenation-induced replication restart. Cells exposed to these levels of hypoxia are however sensitive to loss of Chk1. This suggests a new role for Chk1 in the cell cycle response to reoxygenation.

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Section: Chk1 Signalling In Hypoxia/reoxygenationmentioning

confidence: 61%

Exposure to acute hypoxia induces a transient DNA damage response which includes Chk1 and TLK1

Pires¹,

Bencokova²,

McGurk³

et al. 2010

Cell Cycle

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“…Anoxia can induce an ATM-and ATR-mediated G 1 and intra-S (DNA replicative) arrest and a further G 2 phase arrest upon reoxygenation (42)(43)(44). This could lead to altered S and G 2 fractions that may bias HR protein expression and function, given that HR is cell cycle dependent (37).…”

Section: Discussionmentioning

confidence: 99%

Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance

et al. 2008

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Hypoxic and/or anoxic tumor cells can have increased rates of mutagenesis and altered DNA repair protein expression. Yet very little is known regarding the functional consequences of any hypoxia-induced changes in the expression of proteins involved in DNA double-strand break repair. We have developed a unique hypoxic model system using H1299 cells expressing an integrated direct repeat green fluorescent protein (DR-GFP) homologous recombination (HR) reporter system to study HR under prolonged chronic hypoxia (up to 72 h under 0.2% O 2 ) without bias from altered proliferation, cell cycle checkpoint activation, or severe cell toxicity. We observed decreased expression of HR proteins due to a novel mechanism involving decreased HR protein synthesis. Error-free HR was suppressed 3-fold under 0.2% O 2 as measured by the DR-GFP reporter system. This decrease in functional HR resulted in increased sensitivity to the DNA cross-linking agents mitomycin C and cisplatin but not to the microtubule-interfering agent, paclitaxel. Chronically hypoxic H1299 cells that had decreased functional HR were relatively radiosensitive [oxygen enhancement ratio (OER), 1.37] when compared with acutely hypoxic or anoxic cells (OER, 1.96-2.61). Using CAPAN1 cells isogenic for BRCA2 and siRNA to RAD51, we confirmed that the hypoxia-induced radiosensitivity was due to decreased HR capacity. Persistent down-regulation of HR function by the tumor microenvironment could result in low-fidelity DNA repair and have significant implications for response to therapy and genetic instability in human cancers. [Cancer Res 2008;68(2):605-14]

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“…Previous studies have reported that the ATM and ATR kinases are activated under severe hypoxia or anoxia (,0.1% O 2 ) (Bencokova et al, 2009;Freiberg et al, 2006;Gibson et al, 2005;Hammond et al, 2004). This could bias the use of c-H2AX as a biomarker of exogenous DNA-dsbs under hypoxic conditions, given its dependence on ATM.…”

Section: G0-g1 Synchronized Fibroblasts Represent a Robust Model To Smentioning

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

111

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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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Hypoxia-Induced Phosphorylation of Chk2 in an Ataxia Telangiectasia Mutated–Dependent Manner

Cited by 81 publications

References 33 publications

Exposure to acute hypoxia induces a transient DNA damage response which includes Chk1 and TLK1

Exposure to acute hypoxia induces a transient DNA damage response which includes Chk1 and TLK1

Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance

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

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