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Tumor hypoxia as a driving force in genetic instability

Kaisa R Luoto, Ramya Kumareswaran, Robert G Bristow

Genome Integrity · 2013 · Review

doi:10.1186/2041-9414-4-5

Abstract

Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an adverse impact on patient prognosis. Tumor hypoxia can increase metastatic capacity and lead to resistance to chemotherapy and radiotherapy. Hypoxia also leads to altered transcription and translation of a number of DNA damage response and repair genes. This can lead to inhibition of recombination-mediated repair of DNA double-strand breaks. Hypoxia can also increase the rate of mutation. Therefore, tumor cell adaptation to the hypoxic microenvironment can drive genetic instability and malignant progression. In this review, we focus on hypoxia-mediated genetic instability in the context of aberrant DNA damage signaling and DNA repair. Additionally, we discuss potential therapeutic approaches to specifically target repair-deficient hypoxic tumor cells.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

The tumor microenvironment is characterized by sub-regions of nutrient deprivation, low extracellular pH, high interstitial fluid pressure, and hypoxia. Hypoxic areas arise when oxygen consumption exceeds that of supply. In normal tissues, the oxygen supply matches the metabolic requirements of the cells. However, in locally advanced solid tumors, the oxygen consumption increases significantly, resulting in inadequate oxygen supply to some regions of the tumor. In addition, the blood vessels within a tumor microenvironment are usually chaotic, dilated and irregularly organized. In normal tissues, the oxygen tension (pO2) ranges from 10 to 80 mmHg (or 1.25% to 10% O2). However, tumors often contain regions where the oxygen concentration can significantly decrease to less than 5 mmHg (or < 0.6% O2). Clinical studies using pO2 electrodes, hypoxia imaging (positron emission tomography (PET)), and immunohistochemistry (IHC) have demonstrated that hypoxia is a characteristic of all solid tumors. Hypoxic regions within tumors can be measured by IHC assessment of intrinsic and extrinsic hypoxic cell biomarkers. Intrinsic biomarkers of hypoxic response include hypoxia inducible factor 1 (HIF1α), vascular endothelial growth factor (VEGF), carbonic anhydrase IX (CAIX), osteopontin and glucose transporters 1 and 3 (GLUT1, GLUT3) and the extrinsic biomarkers include drugs that specifically accumulate or become bio-reduced to form adducts within hypoxic cells such as pimonidazole (PIMO), EF5 and CCI-103 F. Increased levels of hypoxia correlates with genetic instability, tumor progression, local and systemic resistance; all leading to poor clinical outcome following treatment.

Tumor cells that lie beyond the diffusion distance for oxygen (> 70 μm away from blood vessels) can quickly outstrip blood supply and are exposed to chronically low oxygen tensions. These diffusion-limited conditions for duration of days are referred to as “prolonged” or “chronic hypoxia”. The cells in these regions are believed to remain hypoxic until they die (due to lack of oxygen or nutrients) or are reoxygenated. Hypoxia can also be transient or “cycling” due to acute perfusion changes in the tumor vasculature. The blood vessels formed during unregulated angiogenesis contain severe structural and functional abnormalities and can temporarily close and re-open, leading to cycles of acute hypoxia/anoxia (from minutes to hours) followed by reoxygenation (hence, cycling hypoxia). Both acute and chronic hypoxia co-exist within a tumor resulting in significant gradients of oxygen consumption leading to intratumor heterogeneity.

In an experimental setting, cellular hypoxia can be induced by placing cultured tumor cells in complete media in environmentally-controlled chambers in which oxygen levels in the gas phase are maintained at 0.01-3%. These hypoxic conditions may not be lethal nor growth inhibitory to selected tumor cell lines when cultured in the presence of excess glucose and nutrients. However, when cells are placed in the complete absence of oxygen (anoxia), most cells will stop proliferating due to the activation of anoxia-mediated intra-S phase arrest mediated by the ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and RAD3-related (ATR) kinases. If prolonged, this arrest of DNA replication becomes irreversible leading to cell death mechanisms. Hence, a permanent anoxic microenvironment (e.g. close to 0% O2) eventually leads to cell death whereas tumor cells that exist in hypoxic microenvironments (e.g. 0.2 to 1% O2) could adapt and continue to proliferate with altered biology. Tumor cells that adapt to low oxygen conditions gain an overall advantage for growth and leads to treatment resistance following chemotherapy or radiotherapy. Therefore, the study of proliferating hypoxic cells is important as it represents a clinically-challenging, sub-population of resistant cells with the potential of clonal expansion and metastatic spread.

Clinical observations, supported by pre-clinical data, have demonstrated that hypoxia is associated with an increased capacity for metastasis. Metastasis is a multi-step process that involves disruption of cell adhesion to the neighboring cells and to the basement membrane, migration through the extracellular matrix, penetration of vessel walls and circulation exit, and finally initiation of angiogenesis to allow tumor growth in the target tissue. Hypoxia can lead to altered expression of many proteins involved in this process by regulating the expression of E-cadherin (cell-cell contact), urokinase-type plasminogen activator receptor (uPAR; degradation of extracellular matrix proteins), hepatocycte growth factor (HGF; cellular motility) and vascular endothelial growth factor (VEGF; angiogenesis and vascular permeability). Hypoxia also limits the effectiveness of many anti-cancer therapies. The efficiency of ionizing radiation to create lethal DNA breaks is strongly associated with oxygen tension and creation of free radicals. Oxygen can react with the damaged DNA bases created by free radicals to yield a more stable adduct and this reaction chemically “fixes” the damage. Indeed, oxygenated cells can be two to three times more sensitive to radiation than hypoxic or anoxic cells. However, ionizing radiation under anoxic conditions has been shown to increase the levels of DNA-protein crosslinks. Moreover, poor drug distribution and decreased proliferation can decrease the efficacy of many chemotherapy drugs. Thus, the cells in hypoxic regions can adapt to become resistant to radiotherapy and chemotherapy and ongoing selection of increasing aggressiveness. Therefore, two main clinical entities are associated with hypoxic tumors: increased local tumor cell resistance and development of systemic metastasis. Despite these data, hypoxia-targeted therapy is still not a standard of current cancer treatments. Therefore, the study of hypoxic cells is important in order to gain a further understanding of the consequences of the hypoxic microenvironment for the development of genetic instability as a precursor to tumor progression and therapy-associated resistance.

Hypoxia-mediated genetic instability

Tumor cells can acquire multiple adaptations in the selective pressure of the tumor microenvironment. Hypoxia inducible factor 1α (HIF1α) is a transcription factor, which is kept at low levels in the presence of oxygen by von Hippel-Lindau protein (VHL)-mediated degradation. In hypoxic conditions, HIF1α is quickly stabilized and regulates a number of genes including those involved in vascularization, glycolysis and pH homeostasis. HIF1α is crucial for hypoxic adaptation, and overexpression of HIF1α is associated with a poor disease outcome. Loss of HIF1α control can promote the malignant phenotype and genomic instability via interplay with oncoproteins such as c-MYC. Oncogene amplification, DNA replication stress, and deregulated DNA damage checkpoint signaling in hypoxic tumor cells, together with the ability to escape cell death, can allow cells to proliferate in the presence of damaged DNA and acquire further mutations. The vicious cycle is accelerated by increased frequency of mutations and by the ability of hypoxic cells to downregulate DNA repair; therefore further driving genomic instability (see Figure 1). Moreover, when hypoxic cells become reoxygenated, they may acquire further DNA damage as a result of a sudden burst of free radicals. We now discuss further hypoxia-mediated genomic instability in the context of the DNA damage signaling and inhibited DNA repair.

Hypoxia and the DNA Damage Response (DDR): checkpoints and DNA replication

Human cells maintain genetic integrity by detecting DNA damage and activating cell cycle checkpoints and DNA repair pathways. The G1/S, intra-S, and the G2/M checkpoints, are mediated by ATM/ATR and checkpoint kinases 2 and 1 (CHK2)/(CHK1), respectively. These kinases transmit signals to the effector molecules p53, p21 (G1/S) and CDC25 (G1/S, intra-S and G2/M) to prevent cell cycle progression or to initiate programmed cell death. Cycles of hypoxia followed by reoxygenation in tumors cyclically activates many DNA damage response (DDR) proteins. Furthermore, ATM, DNA-PKcs, H2AX, p53, CHK1, CHK2, 53BP1 and NBS1 are phosphorylated under conditions of severe hypoxia (<0.02%) in the absence of exogenous DNA damage. Anoxia therefore leads to cell cycle arrests at G1 and intra-S in the absence of DNA damage, and in turn, reoxygenation causes CHK2-mediated G2 arrest. When an arrested hypoxic cell becomes reoxygenated, it may either resume proliferation or undergo an irreversible loss of DNA replication ability and undergo cell death. The length of the hypoxic stress may determine the ultimate fate of a cancer cell. Cell cycle changes however depend on the level of hypoxia. For example, oxygen levels such as 0.2% do not activate ATM or ATR and cell cycle checkpoint signaling. Propagation of such a tumor cell with potentially altered DNA damage signaling and reoxygenation-induced DNA damage, can contribute to genetic instability and malignant progression.

HIF1α can also bind directly to minichromosome maintenance (MCM) proteins that are responsible for unwinding the DNA during replication. Direct interaction between HIF1α and MCM7 results in increased prolyl hydroxylation-dependent HIF1α degradation, and an interaction with MCM3 results in HIF1α transactivation domain function inhibition. HIF1α can block replication origin firing and DNA replication by binding to Cdc6, which is involved in recruiting MCM helicases to replication origins. HIF1α-Cdc6 interaction leads to enhanced MCM helicase loading and decreased recruitment of Cdc7 to replication origins, resulting inhibition of replication origin firing and overall DNA replication.

Hypoxia causes microsatellite and chromosomal instability

Studies have also documented an increased rate of spontaneous DNA mutations in cells exposed to hypoxia using reporter assays. This further supports the view of tumor microenvironment as a driving force of genomic instability (see Table 1). The concept of genetic instability covers a wide variety of genetic alterations from point mutations to chromosomal number. These changes are divided into two types: microsatellite instability (MSI) and chromosomal instability. MSI is typically found in colorectal cancers and is caused by defective DNA mismatch repair (MMR). As hypoxia downregulates MMR, a model of tumor microenvironment-driven MSI has been proposed. This suggestion is supported by studies both in vitro and in vivo of colorectal cancer models. High level of HIF1α associates with MSI in human colorectal carcinoma. Further investigation in clinical settings will show whether the mechanistic laboratory findings of HIF-MMR-MSI can be generalized to other cancers in addition to colon carcinomas.

DNA double-strand break (DSB) repair is crucial for chromosomal integrity. Unrepaired DSBs can lead to formation of deletions, insertions, translocations and amplifications. For example, cells deficient for BRCA1/2 develop spontaneous gross chromosomal aberrations. Hypoxia is known to both inhibit DSB repair and to promote chromosomal instability in multiple ways. Fragile sites are specific chromosomal regions prone to chromosomal breakage and rearrangements during replication stress and are induced under hypoxia. This could be, in part, explained by hypoxia-mediated downregulation of DSB repair genes, as RNAi inhibition of DSB repair results in fragile site activation. Additionally, ATM and ATR kinases maintain fragile site stability, and DSB biomarkers γ-H2AX and DNA-PKcsThr2609 foci localize at fragile sites. An unrepaired DSB can also lead to DNA amplification, which has been observed in hypoxic cells. Additionally, the frequency of sister chromatid exchange (SCE), which is in part controlled by homologous recombination (HR) repair, may be increased in hypoxic primary human lymphocytes. Human fibroblasts subjected to continual hypoxic conditions following exogenous DNA damage maintained increased chromosomal aberrations such as chromosome breaks, chromatid breaks, ring chromosomes, telomeric fusions, reciprocal translocations and double minutes. Finally, hypoxia may also induce global deacetylation and methylation of histones, phosphorylation of H2AX and altered condensation states within the chromatin.

In order to prevent mitotic errors leading to genetic instability, the cell must properly align chromosomes during mitosis. The mitotic spindle is generated by the activity of centrosomes, which are composed of centrioles and pericentriolar material. Defects in centrosomes and spindle formation lead to aneuploidy during the process of carcinogenesis and tumor progression. Recently, a study has shown that hypoxia can modify centrosome function by altering the activity of prolyl-4-hydroxylases (PHDs) towards the protein Cep192 (a critical component of the centrosome). This allows for mediating signaling between oxygen tension and cell cycle control. Further studies are required to investigate whether these and other genes that are involved in mitosis and centrosome organization are altered in cancer cells within hypoxic sub-regions of solid tumors.

Altogether, these studies support the concept that hypoxia can modify fragile sites, the repair of DNA damage, chromatin biology, and possibly mitosis in promoting genetic instability during tumor progression.

Hypoxia-mediated inhibition of DNA repair

The understanding of hypoxia in the context of signaling and DNA repair is increasing based on data using isogenic models that vary in specific DNA repair pathways. Below, we discuss the mechanisms of DNA repair downregulation in hypoxic cells in a pathway-specific manner (Figure 1).

DNA double-strand break repair

Ionizing radiation (IR) or radiomimetic drugs create DSBs, which are mainly repaired by HR or non-homologous end-joining (NHEJ) pathways in a cell cycle-dependent manner. The proteins RAD51, BRCA1/2 and the MRN complex (MRE11, RAD50, NBS1) together regulate HR during S and G2 phases of the cell cycle. Proteins such as KU70/80, DNA-PKcs and DNA-ligase IV function in NHEJ across all phases of the cell cycle.

The majority of HR proteins are repressed by chronic hypoxia. This can occur through decreased transcription, translation, miRNA modulation and epigenetic silencing. The first mechanistic model suggests that HIF1α competes with and opposes MYC activity in hypoxic cells, inhibiting Brca1 and Nbs1 transcription. Another model proposes that HR gene expression, including Rad51 and Brca1, is repressed by the E2F-4/p130 complex independent of HIF. The HIF-independent mechanism is supported by observations of downregulated RAD51 in isogenic HIF1α−/− mouse embryo fibroblasts (MEFs) under hypoxia, albeit by reduced efficiency. Studies from our laboratory support a third model involving selective inhibition of protein synthesis. Hypoxia alters protein synthesis by pathways that modulate gene expression in both transcript-specific and a global manner; via unfolded protein response (UPR) and mammalian target of rapamycin (mTOR) signaling. Our findings indicate that in chronically hypoxic proliferating cells, RAD51 and BRCA2 are downregulated due to selective inhibition of mRNA translation. Yet another layer to hypoxia-regulated HR expression involves altered chromatin modification and Brca1 promoter silencing in severe hypoxia. Finally, miRNA may play a role in HR suppression and can affect Rad52 gene expression.

The impact of hypoxia and DNA repair on malignant progression is demonstrated in studies indicating that repressed HR is linked with cancer initiating cell formation. Breast tumor-initiating cells overexpress polycomb protein EZH2, which is further induced by HIF1α under hypoxia. EZH2 inhibits Rad51 transcription in hypoxic CD44+CD24-/low cells, which is associated with increased genomic abnormality. This EZH2-RAD51 signaling (via RAF1 amplification) promotes mammosphere formation and malignant progression.

The function of NHEJ in hypoxia-driven genetic instability and radiation response is more controversial. Inhibited expression of DNA-PKcs, Ku70, Ku80 and DNA-ligase IV has been observed under hypoxia. NHEJ factors are downregulated in hypoxic wild-type MEFs and in normoxic HIF1α−/− MEFs. In cervical tumors, KU70/KU80 expression correlates with oxygen pressure and is inhibited with increasing distance to blood vessels. We observed an increase in residual DSBs in G0/G1 synchronized human fibrobalsts under hypoxic conditions following exogenous DNA damage (Figures 2 and 3). On the other hand, induction of Ku70 may occur under hypoxia in some cell lines. KU70 could indeed contribute to hypoxic tumor cell resistance to radiation, as expression of a dominant negative form of KU70 sensitizes hypoxic glioma and colorectal cells to radiation. Other reports have proposed redundancy or increased NHEJ under hypoxia. An outstanding question in the field is whether the MRN complex, ATM and DNA-PKcs kinases differentially sense DSBs under oxia vs hypoxia (Figure 1). Varying model systems and tumor microenvironment conditions might explain the differing observations, and further investigation will clarify the role of hypoxia in NHEJ control.

Mismatch repair

MMR repairs DNA base substitutions and misalignments, which occur during DNA replication. Mammalian MMR uses proteins such as MutSα (MSH2 + MSH6), MutSβ (MSH2 + MSH3), and MutLα (MLH1 + PMS2).

The involvement of MMR in the hypoxic response is fairly well characterized. The hypoxia-driven genetic instability in colorectal cancers is consistent with inhibited Mlh1 transcription in low oxygen. Mechanistically, MMR inhibition under hypoxia involves at least MYC and DEC transcription factors. Interplay of HIF1α and MYC has been suggested to regulate MMR expression; MYC-dependent regulation of MSH2 and MSH6 in oxic cells may be replaced by HIF1α under hypoxia. In addition, knockdown of HIF1α reverses hypoxia-driven inhibition of MMR expression. Repression of MMR gene expression by decreased MYC and increased MAX, MAD and MNT association on Mlh1 and Msh2 promoters have been observed in hypoxic cells. MYC, MAD and MNT (as part of the “max network” containing basic helix-loop-helix zipper (bHLHZ) motifs) form heterodimers with MAX resulting in sequence-specific DNA binding. These DNA-bound heterodimers can then alter chromatin structure to modulate transcription. Additionally, hypoxia-induced transcription repressors DEC1 and DEC2 contribute to Mlh1 inhibition. Hypoxic MMR regulation is also influenced by the state of chromatin acetylation.

Nucleotide excision repair and Fanconi anemia pathway

Chemicals covalently bound to DNA forming bulky adducts, as well as chemical-caused DNA crosslinks and UV-induced DNA lesions, are repaired by nucleotide excision repair (NER). NER in mammals uses two pathways: global genome repair (GGR) and transcription-coupled repair (TCR). GGR involves multiple sequential steps including sensing of the lesion (XPC-HR23B-Centrin 2 complex), opening of a denaturation bubble (TFIIH, XPA-RPA complex), incision of damaged strand (XPG, XPF-ERCC1 complex), displacement of lesion-containing oligonucleotides and gap filling (DNA Pol δ and ϵ) and ligation (ligase III, ligase I). On the other hand, TCR requires CSA, CSB and XAB2 to sense the lesion and proceeds to GGR for the next sequential steps. Both decreased and increased ability of cells to repair UV-damaged DNA in conditions of hypoxia and low pH have been reported. Indication for NER in the hypoxic response comes from findings of XPC and XPD as direct HIF1α targets, and inhibition of HIF1α perturbs the removal of UVB-induced 6–4 photoproducts (6-4PPs) and cyclobutane pyrimidine dimers (CPDs). Also, HIF1α associates with the gene promoter of CSB/ERCC6, which functions in recruiting NER repair proteins to the damaged DNA, and is induced by hypoxia. CSB mutant cells fail to activate HIF-dependent hypoxic response. Finally, RAD23B protein is repressed under hypoxia and by miRNA-373. Further investigation is needed to establish the role of hypoxia in NER.

Fanconi anemia (FA) is a hereditary disorder with predisposition to cancer. The FA pathway includes 14 FANC genes, which function in ubiquitination-phosphorylation pathways and participate in repairing DNA interstrand crosslinks created by agents such as (mitomycin C) MMC or cisplatin. Little is known regarding the role of FANC in the hypoxic response. However, FANCC and FANCD2 cells exhibit increased IR sensitivity under hypoxia compared to wild-type cells. UBE2T is an E2 conjugating enzyme that operates in the FA pathway to mono-ubiquitinate FANCD2 and FANCI. UBE2T expression is inhibited under hypoxia by a mechanism involving decreased promoter activity, independent of HIF1α, HIF1β or HIF2α. Consistent with the FA phenotype, both anoxic and UBE2T knockdown cells are hypersensitive to MMC-induced DNA crosslinks.

Therapeutic targeting of hypoxic tumor cells

The success of anti-cancer therapies is currently challenged by increased local and systemic resistance of tumor cells residing in the hypoxic microenvironment. However, the hypoxic phenotype can also provide an opportunity to specifically target cells in the tumor microenvironment and improve the therapeutic index (e.g. kill more cancer cells than normal cells) (see Figure 4). The development of therapeutic agents that are selectively activated upon exposure to low oxygen is of great interest. For example, tirapazamine and apaziquone, both bioreductive prodrugs that induce DNA damage, have been tested in Phase III clinical trials. A newer compound, TH-302, is a 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM), which causes DNA damage under hypoxic/anoxic conditions. The antitumor activity of TH-302 has been shown to be dose-dependent and decreased the hypoxic fraction in xenografts of varying histology. TH-302 also induces DNA damage (as measured by γ-H2AX) in hypoxic regions in vivo and can further kill cells through a time-dependent “bystander effect”. This compound is currently in Phase II-III clinical trials in combination with chemotherapy.

Translational control is an important contributor to the hypoxic adaptation and gene expression alongside with HIF-dependent pathways. Therefore, targeting mTOR and UPR could provide another opportunity to enhance selective tumor cell kill. Clinically relevant agents that influence mTOR or UPR signaling include for example imatinib, nelfinavir and sunitinib, which can improve tumor oxygenation and inhibit angiogenesis.

Synthetic lethality is a phenomenon that arises when mutations in two or more genes result in cell death, while a cell with a mutation in either gene alone is viable. Over the recent years, this has started to attract attention as a way to attack the Achilles’ heel of a cancer cell. For example, inhibition of poly(ADP-ribose) polymerase (PARP), which normally functions in single-strand break (SSB) and base-excision repair (BER), is synthetically lethal with BRCA-deficient tumors. In addition to targeting cancerous mutations, synthetic lethality based on tumor microenvironment has emerged, where the extrinsic differences of tumor cells are used to widen the therapeutic index. In this “contextual” synthetic lethality, the hypoxic phenotype with defective DNA repair can be exploited, together with inhibiting a backup DNA repair pathway, to specifically kill hypoxic cells. Therapies would therefore preferentially kill tumor cells with reduced DNA repair capacity, and spare normal tissue with physiological oxygenation state and functional DNA repair. Indeed, hypoxic HR-defective cells are sensitive to PARP inhibition. PARP inhibition induces DNA damage in proliferating cells and kills hypoxic cells specifically in S phase. Synthetic lethality in the HR pathway has also been documented between RAD52 and BRCA2, as well as between splicing factor proline and glutamate-rich (SFPQ)/PSF and RAD51D. Additionally, PTEN null astrocytes were found to be sensitive to PARP inhibition due to lower expression of Rad51B-D. However, recent data from our laboratory failed to observe a correlation between PTEN status and RAD51 function.

In MMR, inhibition of POLB in MSH2-deficient; and inhibition of POLG in MLH1-deficient cells, produces a synthetic lethal phenotype. An siRNA screen identified inhibited PTEN-induced putative kinase 1 (PINK1) as lethal in cells deficient in MLH1, MSH2 and MSH6. Given that most HR factors and MMR are downregulated under hypoxia, determining whether these synthetic lethal interactions could be exploited to target hypoxic tumor cells, would be of great interest. Future investigations will show if these observations could have an impact on radiation- and clinical oncology.

Conclusions

A number of molecular mechanisms have been proposed to explain hypoxic inhibition of HR and MMR-mediated DNA repair based on biochemical and cell biology endpoints. Molecular pathways may play differing roles depending on tissue type, microenvironment conditions and proliferation status; or alternatively, each might have a relative contribution for a global DNA repair-deficient phenotype. Dissecting these pathways could help designing anti-cancer treatments that inhibit DNA repair and sensitize tumor cells to radio- and chemotherapies. Also, a better understanding of therapies targeting the proliferating hypoxic cell subpopulations could increase selective killing of resistant tumor cells. Clinical trials using these approaches will require careful assessment of the tumor microenvironment using imaging or other techniques in order to incorporate hypoxia assessment as a part of a standard of care. This approach will serve well to be one step closer to individualized cancer medicine and improved patient outcome.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

KRL, RK and RGB wrote the manuscript. All authors read and approved the final manuscript.

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  38. 38.

    Pires IM Bencokova Z Milani M Folkes LK Li JL Stratford MR Harris AL Hammond EM Effects of acute versus chronic hypoxia on DNA damage responses and genomic instabilityCancer Res2010 4925935

    Not in our library10.1158/0008-5472.can-09-2715

  39. 39.

    Zafarana G Ishkanian AS Malloff CA Locke JA Sykes J Thoms J Lam WL Squire JA Yoshimoto M Ramnarine VR Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapyCancer2012 440534062

    Not in our library10.1002/cncr.26729

  40. 40.

    Huang LE Bindra RS Glazer PM Harris AL Hypoxia-induced genetic instability–a calculated mechanism underlying tumor progressionJ Mol Med2007 4139148

    Not in our library10.1007/s00109-006-0133-6

  41. 41.

    Hammond EM Dorie MJ Giaccia AJ ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenationJ Biol Chem2003 41220712213

    Not in our library10.1074/jbc.m212360200

  42. 42.

    Hsieh CH Shyu WC Chiang CY Kuo JW Shen WC Liu RS NADPH oxidase subunit 4-mediated reactive oxygen species contribute to cycling hypoxia-promoted tumor progression in glioblastoma multiformePLoS One2011 4e23945

    Not in our library10.1371/journal.pone.0023945

  43. 43.

    O”Driscoll M Jeggo PA The role of double-strand break repair - insights from human geneticsNat Rev Genet2006 44554

    Not in our library10.1038/nrg1746

  44. 44.

    Shimada M Nakanishi M DNA damage checkpoints and cancerJ Mol Histol2006 4253260

    Not in our library10.1007/s10735-006-9039-4

  45. 45.

    Li L Zou L Sensing, signaling, and responding to DNA damage: organization of the checkpoint pathways in mammalian cellsJ Cell Biochem2005 4298306

    Not in our library10.1002/jcb.20355

  46. 46.

    Hammond EM Denko NC Dorie MJ Abraham RT Giaccia AJ Hypoxia links ATR and p53 through replication arrestMol Cell Biol2002 418341843

    Not in our library10.1128/mcb.22.6.1834-1843.2002

  47. 47.

    Gibson SL Bindra RS Glazer PM Hypoxia-induced phosphorylation of Chk2 in an ataxia telangiectasia mutated-dependent mannerCancer Res2005 41073410741

    Not in our library10.1158/0008-5472.can-05-1160

  48. 48.

    Freiberg RA Krieg AJ Giaccia AJ Hammond EM Checking in on hypoxia/reoxygenationCell Cycle2006 413041307

    Not in our library10.4161/cc.5.12.2811

  49. 49.

    Bouquet F Ousset M Biard D Fallone F Dauvillier S Frit P Salles B Muller C A DNA-dependent stress response involving DNA-PK occurs in hypoxic cells and contributes to cellular adaptation to hypoxiaJ Cell Sci2011 419431951

    Not in our library10.1242/jcs.078030

  50. 50.

    Harding SM Coackley C Bristow RG ATM-dependent phosphorylation of 53BP1 in response to genomic stress in oxic and hypoxic cellsRadiother Oncol2011 4307312

    Not in our library10.1016/j.radonc.2011.05.039

  51. 51.

    Kim BM Choi JY Kim YJ Woo HD Chung HW Reoxygenation following hypoxia activates DNA-damage checkpoint signaling pathways that suppress cell-cycle progression in cultured human lymphocytesFEBS Lett2007 430053012

    Not in our library10.1016/j.febslet.2007.05.053

  52. 52.

    Gardner LB Li Q Park MS Flanagan WM Semenza GL Dang CV Hypoxia inhibits G1/S transition through regulation of p27 expressionJ Biol Chem2001 479197926

    Not in our library10.1074/jbc.m010189200

  53. 53.

    Gardner LB Li F Yang X Dang CV Anoxic fibroblasts activate a replication checkpoint that is bypassed by E1aMol Cell Biol2003 490329045

    Not in our library10.1128/mcb.23.24.9032-9045.2003

  54. 54.

    Wang L Gao J Dai W Lu L Activation of Polo-like kinase 3 by hypoxic stressesJ Biol Chem2008 42592825935

    Not in our library10.1074/jbc.m801326200

  55. 55.

    Tan C Zhang LY Chen H Xiao L Liu XP Zhang JX Overexpression of the human ubiquitin E3 ligase CUL4A alleviates hypoxia-reoxygenation injury in pheochromocytoma (PC12) cellsBiochem Biophys Res Commun2011 4403408

    Not in our library10.1016/j.bbrc.2011.11.054

  56. 56.

    Chan N Koritzinsky M Zhao H Bindra R Glazer PM Powell S Belmaaza A Wouters B Bristow RG Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistanceCancer Res2008 4605614

    Not in our library10.1158/0008-5472.can-07-5472

  57. 57.

    Hubbi ME Kshitiz Gilkes DM Rey S Wong CC Luo W Kim DH Dang CV Levchenko A Semenza GL A nontranscriptional role for HIF-1alpha as a direct inhibitor of DNA replicationSci Signal2013 4ra10

    Not in our library10.1126/scisignal.2003417

  58. 58.

    Hubbi ME Luo W Baek JH Semenza GL MCM proteins are negative regulators of hypoxia-inducible factor 1Mol Cell2011 4700712

    Not in our library10.1016/j.molcel.2011.03.029

  59. 59.

    Papp-Szabo E Josephy PD Coomber BL Microenvironmental influences on mutagenesis in mammary epithelial cellsInt J Cancer2005 4679685

    Not in our library10.1002/ijc.21088

  60. 60.

    Keysar SB Trncic N Larue SM Fox MH Hypoxia/reoxygenation-induced mutations in mammalian cells detected by the flow cytometry mutation assay and characterized by mutant spectrumRadiat Res2010 42126

    Not in our library10.1667/rr1838.1

  61. 61.

    Reynolds TY Rockwell S Glazer PM Genetic instability induced by the tumor microenvironmentCancer Res1996 457545757

    Not in our library

  62. 62.

    Li CY Little JB Hu K Zhang W Zhang L Dewhirst MW Huang Q Persistent genetic instability in cancer cells induced by non-DNA-damaging stress exposuresCancer Res2001 4428432

    Not in our library

  63. 63.

    Michor F Iwasa Y Vogelstein B Lengauer C Nowak MA Can chromosomal instability initiate tumorigenesis?Semin Cancer Biol2005 44349

    Not in our library10.1016/j.semcancer.2004.09.007

  64. 64.

    Geiersbach KB Samowitz WS Microsatellite instability and colorectal cancerArch Pathol Lab Med2011 412691277

    Not in our library10.5858/arpa.2011-0035-ra

  65. 65.

    Shahrzad S Quayle L Stone C Plumb C Shirasawa S Rak JW Coomber BL Ischemia-induced K-ras mutations in human colorectal cancer cells: role of microenvironmental regulation of MSH2 expressionCancer Res2005 481348141

    Not in our library10.1158/0008-5472.can-05-0713

  66. 66.

    Edwards RA Witherspoon M Wang K Afrasiabi K Pham T Birnbaumer L Lipkin SM Epigenetic repression of DNA mismatch repair by inflammation and hypoxia in inflammatory bowel disease-associated colorectal cancerCancer Res2009 464236429

    Not in our library10.1158/0008-5472.can-09-1285

  67. 67.

    Kondo A Safaei R Mishima M Niedner H Lin X Howell SB Hypoxia-induced enrichment and mutagenesis of cells that have lost DNA mismatch repairCancer Res2001 476037607

    Not in our library

  68. 68.

    Furlan D Sahnane N Carnevali I Cerutti R Bertoni F Kwee I Uccella S Bertolini V Chiaravalli AM Capella C Up-regulation of the hypoxia-inducible factor-1 transcriptional pathway in colorectal carcinomasHum Pathol2008 414831494

    Not in our library10.1016/j.humpath.2008.02.013

  69. 69.

    Lehtonen HJ Makinen MJ Kiuru M Laiho P Herva R van Minderhout I Hogendoorn PC Cornelisse C Devilee P Launonen V Aaltonen LA Increased HIF1 alpha in SDH and FH deficient tumors does not cause microsatellite instabilityInt J Cancer2007 413861389

    Not in our library10.1002/ijc.22819

  70. 70.

    Rice GC Hoy C Schimke RT Transient hypoxia enhances the frequency of dihydrofolate reductase gene amplification in Chinese hamster ovary cellsProc Natl Acad Sci U S A1986 459785982

    Not in our library10.1073/pnas.83.16.5978

  71. 71.

    Young SD Marshall RS Hill RP Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cellsProc Natl Acad Sci U S A1988 495339537

    Not in our library10.1073/pnas.85.24.9533

  72. 72.

    Rofstad EK Johnsen NM Lyng H Hypoxia-induced tetraploidisation of a diploid human melanoma cell line in vitroBr J Cancer Suppl1996 4S136S139

    Not in our library

  73. 73.

    Coquelle A Toledo F Stern S Bieth A Debatisse M A new role for hypoxia in tumor progression: induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRsMol Cell1998 4259265

    Not in our library10.1016/s1097-2765(00)80137-9

  74. 74.

    Yuan J Narayanan L Rockwell S Glazer PM Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pHCancer Res2000 443724376

    Not in our library

  75. 75.

    Coquelle A Rozier L Dutrillaux B Debatisse M Induction of multiple double-strand breaks within an hsr by meganucleaseI-SceI expression or fragile site activation leads to formation of double minutes and other chromosomal rearrangementsOncogene2002 476717679

    Not in our library10.1038/sj.onc.1205880

  76. 76.

    Mihaylova VT Bindra RS Yuan J Campisi D Narayanan L Jensen R Giordano F Johnson RS Rockwell S Glazer PM Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cellsMol Cell Biol2003 432653273

    Not in our library10.1128/mcb.23.9.3265-3273.2003

  77. 77.

    Banath JP Sinnott L Larrivee B MacPhail SH Olive PL Growth of V79 cells as xenograft tumors promotes multicellular resistance but does not increase spontaneous or radiation-induced mutant frequencyRadiat Res2005 4733744

    Not in our library10.1667/3474.1

  78. 78.

    Koshiji M To KK Hammer S Kumamoto K Harris AL Modrich P Huang LE HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expressionMol Cell2005 4793803

    Not in our library10.1016/j.molcel.2005.02.015

  79. 79.

    Fischer U Radermacher J Mayer J Mehraein Y Meese E Tumor hypoxia: impact on gene amplification in glioblastomaInt J Oncol2008 4509515

    Not in our library

  80. 80.

    Rodriguez-Jimenez FJ Moreno-Manzano V Lucas-Dominguez R Sanchez-Puelles JM Hypoxia causes downregulation of mismatch repair system and genomic instability in stem cellsStem Cells2008 420522062

    Not in our library10.1634/stemcells.2007-1016

  81. 81.

    Lee JH Choi IJ Song DK Kim DK Genetic instability in the human lymphocyte exposed to hypoxiaCancer Genet Cytogenet2010 48388

    Not in our library10.1016/j.cancergencyto.2009.09.002

  82. 82.

    Kumareswaran R Ludkovski O Meng A Sykes J Pintilie M Bristow RG Chronic hypoxia compromises repair of DNA double-strand breaks to drive genetic instabilityJ Cell Sci2012 4189199

    Not in our library10.1242/jcs.092262

  83. 83.

    Mondello C Smirnova A Giulotto E Gene amplification, radiation sensitivity and DNA double-strand breaksMutat Res2010 42937

    Not in our library10.1016/j.mrrev.2010.01.008

  84. 84.

    Popp HD Bohlander SK Genetic instability in inherited and sporadic leukemiasGenes Chromosomes Cancer2010 410711081

    Not in our library10.1002/gcc.20823

  85. 85.

    Patel KJ Yu VP Lee H Corcoran A Thistlethwaite FC Evans MJ Colledge WH Friedman LS Ponder BA Venkitaraman AR Involvement of Brca2 in DNA repairMol Cell1998 4347357

    Not in our library10.1016/s1097-2765(00)80035-0

  86. 86.

    Yu VP Koehler M Steinlein C Schmid M Hanakahi LA van Gool AJ West SC Venkitaraman AR Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivationGenes Dev2000 414001406

    Not in our library

  87. 87.

    Venkitaraman AR Linking the cellular functions of BRCA genes to cancer pathogenesis and treatmentAnnu Rev Pathol2009 4461487

    Not in our library10.1146/annurev.pathol.3.121806.151422

  88. 88.

    Walsh CS Ogawa S Scoles DR Miller CW Kawamata N Narod SA Koeffler HP Karlan BY Genome-wide loss of heterozygosity and uniparental disomy in BRCA1/2-associated ovarian carcinomasClin Cancer Res2008 476457651

    Not in our library10.1158/1078-0432.ccr-08-1291

  89. 89.

    Min J Choi ES Hwang K Kim J Sampath S Venkitaraman AR Lee H The Breast Cancer Susceptibility Gene BRCA2 Is Required for the Maintenance of Telomere HomeostasisJ Biol Chem2012 450915101

    Not in our library10.1074/jbc.m111.278994

  90. 90.

    Johnson AB Barton MC Hypoxia-induced and stress-specific changes in chromatin structure and functionMutat Res2007 4149162

    Not in our library10.1016/j.mrfmmm.2006.10.007

  91. 91.

    Arlt MF Durkin SG Ragland RL Glover TW Common fragile sites as targets for chromosome rearrangementsDNA Repair (Amst)2006 411261135

    Not in our library10.1016/j.dnarep.2006.05.010

  92. 92.

    Schwartz M Zlotorynski E Goldberg M Ozeri E Rahat A le Sage C Chen BP Chen DJ Agami R Kerem B Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stabilityGenes Dev2005 427152726

    Not in our library10.1101/gad.340905

  93. 93.

    Ozeri-Galai E Schwartz M Rahat A Kerem B Interplay between ATM and ATR in the regulation of common fragile site stabilityOncogene2008 421092117

    Not in our library10.1038/sj.onc.1210849

  94. 94.

    Tanaka H Yao MC Palindromic gene amplification–an evolutionarily conserved role for DNA inverted repeats in the genomeNat Rev Cancer2009 4216224

    Not in our library10.1038/nrc2591

  95. 95.

    Wilson DM 3rd Thompson LH Molecular mechanisms of sister-chromatid exchangeMutat Res2007 41123

    Not in our library10.1016/j.mrfmmm.2006.11.017

  96. 96.

    Avidor-Reiss T Gopalakrishnan J Building a centrioleCurr Opin Cell Biol2013 47277

    Not in our library10.1016/j.ceb.2012.10.016

  97. 97.

    Chan JY A clinical overview of centrosome amplification in human cancersInt J Biol Sci2011 411221144

    Not in our library10.7150/ijbs.7.1122

  98. 98.

    Duijf PH Benezra R The cancer biology of whole-chromosome instabilityOncogene2013 447274736

    Not in our library10.1038/onc.2012.616

  99. 99.

    Moser SC Bensaddek D Ortmann B Maure JF Mudie S Blow JJ Lamond AI Swedlow JR Rocha S PHD1 Links Cell-Cycle Progression to Oxygen Sensing through Hydroxylation of the Centrosomal Protein Cep192Dev Cell2013 4381392

    Not in our library10.1016/j.devcel.2013.06.014

  100. 100.

    Bristow RG Ozcelik H Jalali F Chan N Vesprini D Homologous recombination and prostate cancer: a model for novel DNA repair targets and therapiesRadiother Oncol2007 4220230

    Not in our library10.1016/j.radonc.2007.04.016

  101. 101.

    Meng AX Jalali F Cuddihy A Chan N Bindra RS Glazer PM Bristow RG Hypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cellsRadiother Oncol2005 4168176

    Not in our library10.1016/j.radonc.2005.06.025

  102. 102.

    Koshiji M Kageyama Y Pete EA Horikawa I Barrett JC Huang LE HIF-1alpha induces cell cycle arrest by functionally counteracting MycEMBO J2004 419491956

    Not in our library10.1038/sj.emboj.7600196

  103. 103.

    To KK Sedelnikova OA Samons M Bonner WM Huang LE The phosphorylation status of PAS-B distinguishes HIF-1alpha from HIF-2alpha in NBS1 repressionEMBO J2006 447844794

    Not in our library10.1038/sj.emboj.7601369

  104. 104.

    Hayashi M Yoo YY Christensen J Huang LE Requirement of evading apoptosis for HIF-1alpha-induced malignant progression in mouse cellsCell Cycle2011 423642372

    Not in our library10.4161/cc.10.14.16313

  105. 105.

    Bindra RS Schaffer PJ Meng A Woo J Maseide K Roth ME Lizardi P Hedley DW Bristow RG Glazer PM Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cellsMol Cell Biol2004 485048518

    Not in our library10.1128/mcb.24.19.8504-8518.2004

  106. 106.

    Bindra RS Schaffer PJ Meng A Woo J Maseide K Roth ME Lizardi P Hedley DW Bristow RG Glazer PM Alterations in DNA repair gene expression under hypoxia: elucidating the mechanisms of hypoxia-induced genetic instabilityAnn N Y Acad Sci2005 4184195

    Not in our library10.1196/annals.1339.049

  107. 107.

    Bindra RS Glazer PM Co-repression of mismatch repair gene expression by hypoxia in cancer cells: role of the Myc/Max networkCancer Lett2007 493103

    Not in our library10.1016/j.canlet.2006.12.011

  108. 108.

    Chan N Pires IM Bencokova Z Coackley C Luoto KR Bhogal N Lakshman M Gottipati P Oliver FJ Helleday T Contextual synthetic lethality of cancer cell kill based on the tumor microenvironmentCancer Res2010 480458054

    Not in our library10.1158/0008-5472.can-10-2352

  109. 109.

    Wouters BG Koritzinsky M Hypoxia signalling through mTOR and the unfolded protein response in cancerNat Rev Cancer2008 4851864

    Not in our library10.1038/nrc2501

  110. 110.

    Lu Y Chu A Turker MS Glazer PM Hypoxia-Induced Epigenetic Regulation and Silencing of the BRCA1 PromoterMol Cell Biol2011 433393350

    Not in our library10.1128/mcb.01121-10

  111. 111.

    Crosby ME Kulshreshtha R Ivan M Glazer PM MicroRNA regulation of DNA repair gene expression in hypoxic stressCancer Res2009 412211229

    Not in our library10.1158/0008-5472.can-08-2516

  112. 112.

    Chang CJ Yang JY Xia W Chen CT Xie X Chao CH Woodward WA Hsu JM Hortobagyi GN Hung MC EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signalingCancer Cell2011 486100

    Not in our library10.1016/j.ccr.2010.10.035

  113. 113.
    MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1α/HIF-1β · 2010
    No notice
  114. 114.

    Tsuchimoto T Sakata K Someya M Yamamoto H Hirayama R Matsumoto Y Furusawa Y Hareyama M Gene expression associated with DNA-dependent protein kinase activity under normoxia, hypoxia, and reoxygenationJ Radiat Res2011 4464471

    Not in our library10.1269/jrr.10137

  115. 115.

    Wirthner R Wrann S Balamurugan K Wenger RH Stiehl DP Impaired DNA double-strand break repair contributes to chemoresistance in HIF-1 alpha-deficient mouse embryonic fibroblastsCarcinogenesis2008 423062316

    Not in our library10.1093/carcin/bgn231

  116. 116.

    Lara PC Lloret M Clavo B Apolinario RM Bordon E Rey A Falcon O Alonso AR Belka C Hypoxia downregulates Ku70/80 expression in cervical carcinoma tumorsRadiother Oncol2008 4222226

    Not in our library10.1016/j.radonc.2008.07.018

  117. 117.

    He F Li L Kim D Wen B Deng X Gutin PH Ling CC Li GC Adenovirus-mediated expression of a dominant negative Ku70 fragment radiosensitizes human tumor cells under aerobic and hypoxic conditionsCancer Res2007 4634642

    Not in our library10.1158/0008-5472.can-06-1860

  118. 118.

    Sprong D Janssen HL Vens C Begg AC Resistance of hypoxic cells to ionizing radiation is influenced by homologous recombination statusInt J Radiat Oncol Biol Phys2006 4562572

    Not in our library10.1016/j.ijrobp.2005.09.031

  119. 119.

    Bindra RS Gibson SL Meng A Westermark U Jasin M Pierce AJ Bristow RG Classon MK Glazer PM Hypoxia-induced down-regulation of BRCA1 expression by E2FsCancer Res2005 41159711604

    Not in our library10.1158/0008-5472.can-05-2119

  120. 120.

    Madan E Gogna R Pati U p53Ser15 Phosphorylation disrupts p53-RPA70 complex and induces RPA70-mediated DNA repair in hypoxiaBiochem J2012 4811820

    Not in our library10.1042/bj20111627

  121. 121.

    Hoffelder DR Luo L Burke NA Watkins SC Gollin SM Saunders WS Resolution of anaphase bridges in cancer cellsChromosoma2004 4389397

    Not in our library10.1007/s00412-004-0284-6

  122. 122.

    Wimmer K Etzler J Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?Hum Genet2008 4105122

    Not in our library10.1007/s00439-008-0542-4

  123. 123.

    Li J Koike J Kugoh H Arita M Ohhira T Kikuchi Y Funahashi K Takamatsu K Boland CR Koi M Hemmi H Down-regulation of MutS homolog 3 by hypoxia in human colorectal cancerBiochim Biophys Acta2012 4889899

    Not in our library10.1016/j.bbamcr.2012.01.017

  124. 124.

    Grandori C Cowley SM James LP Eisenman RN The Myc/Max/Mad network and the transcriptional control of cell behaviorAnnu Rev Cell Dev Biol2000 4653699

    Not in our library10.1146/annurev.cellbio.16.1.653

  125. 125.

    Nakamura H Tanimoto K Hiyama K Yunokawa M Kawamoto T Kato Y Yoshiga K Poellinger L Hiyama E Nishiyama M Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2Oncogene2008 442004209

    Not in our library10.1038/onc.2008.58

  126. 126.

    Nouspikel T DNA repair in mammalian cells: Nucleotide excision repair: variations on versatilityCell Mol Life Sci2009 49941009

    Not in our library10.1007/s00018-009-8737-y

  127. 127.

    Rezvani HR Mahfouf W Ali N Chemin C Ged C Kim AL de Verneuil H Taieb A Bickers DR Mazurier F Hypoxia-inducible factor-1alpha regulates the expression of nucleotide excision repair proteins in keratinocytesNucleic Acids Res2010 4797809

    Not in our library10.1093/nar/gkp1072

  128. 128.

    Filippi S Latini P Frontini M Palitti F Egly JM Proietti-De-Santis L CSB protein is (a direct target of HIF-1 and) a critical mediator of the hypoxic responseEMBO J2008 425452556

    Not in our library10.1038/emboj.2008.180

  129. 129.

    Kitao H Takata M Fanconi anemia: a disorder defective in the DNA damage responseInt J Hematol2011 4417424

    Not in our library10.1007/s12185-011-0777-z

  130. 130.

    Kuhnert VM Kachnic LA Li L Purschke M Gheorghiu L Lee R Held KD Willers H FANCD2-deficient human fibroblasts are hypersensitive to ionising radiation at oxygen concentrations of 0% and 3% but not under normoxic conditionsInt J Radiat Biol2009 4523531

    Not in our library10.1080/09553000902883810

  131. 131.

    Ramaekers CH van den Beucken T Meng A Kassam S Thoms J Bristow RG Wouters BG Hypoxia disrupts the Fanconi anemia pathway and sensitizes cells to chemotherapy through regulation of UBE2TRadiother Oncol2011 4190197

    Not in our library10.1016/j.radonc.2011.05.059

  132. 132.

    Sun JD Liu Q Wang J Ahluwalia D Ferraro D Wang Y Duan JX Ammons WS Curd JG Matteucci MD Hart CP Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancerClin Cancer Res2012 4758770

    Not in our library10.1158/1078-0432.ccr-11-1980

  133. 133.

    van den Beucken T Magagnin MG Jutten B Seigneuric R Lambin P Koritzinsky M Wouters BG Translational control is a major contributor to hypoxia induced gene expressionRadiother Oncol2011 4379384

    Not in our library10.1016/j.radonc.2011.05.058

  134. 134.

    Zhao H Luoto KR Meng AX Bristow RG The receptor tyrosine kinase inhibitor amuvatinib (MP470) sensitizes tumor cells to radio- and chemo-therapies in part by inhibiting homologous recombinationRadiother Oncol2011 45965

    Not in our library10.1016/j.radonc.2011.08.013

  135. 135.

    Matsumoto S Batra S Saito K Yasui H Choudhuri R Gadisetti C Subramanian S Devasahayam N Munasinghe JP Mitchell JB Krishna MC Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxiaCancer Res2011 463506359

    Not in our library10.1158/0008-5472.can-11-2025

  136. 136.

    Kaelin WG Jr The concept of synthetic lethality in the context of anticancer therapyNat Rev Cancer2005 4689698

    Not in our library10.1038/nrc1691

  137. 137.

    Chalmers AJ Lakshman M Chan N Bristow RG Poly(ADP-ribose) polymerase inhibition as a model for synthetic lethality in developing radiation oncology targetsSemin Radiat Oncol2010 4274281

    Not in our library10.1016/j.semradonc.2010.06.001

  138. 138.

    Hegan DC Lu Y Stachelek GC Crosby ME Bindra RS Glazer PM Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130Proc Natl Acad Sci U S A2010 422012206

    Not in our library10.1073/pnas.0904783107

  139. 139.

    Rajesh C Baker DK Pierce AJ Pittman DL The splicing-factor related protein SFPQ/PSF interacts with RAD51D and is necessary for homology-directed repair and sister chromatid cohesionNucleic Acids Res2011 4132145

    Not in our library10.1093/nar/gkq738

  140. 140.

    Feng Z Scott SP Bussen W Sharma GG Guo G Pandita TK Powell SN Rad52 inactivation is synthetically lethal with BRCA2 deficiencyProc Natl Acad Sci U S A2011 4686691

    Not in our library10.1073/pnas.1010959107

  141. 141.

    McEllin B Camacho CV Mukherjee B Hahm B Tomimatsu N Bachoo RM Burma S PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitorsCancer Res2010 454575464

    Not in our library10.1158/0008-5472.can-09-4295

  142. 142.

    Fraser M Zhao H Luoto KR Lundin C Coackley C Chan N Joshua AM Bismar TA Evans A Helleday T Bristow RG PTEN deletion in prostate cancer cells does not associate with loss of RAD51 function: implications for radiotherapy and chemotherapyClin Cancer Res2012 410151027

    Not in our library10.1158/1078-0432.ccr-11-2189

  143. 143.

    Martin SA McCabe N Mullarkey M Cummins R Burgess DJ Nakabeppu Y Oka S Kay E Lord CJ Ashworth A DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1Cancer Cell2010 4235248

    Not in our library10.1016/j.ccr.2009.12.046

  144. 144.

    Martin SA Hewish M Sims D Lord CJ Ashworth A Parallel high-throughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancersCancer Res2011 418361848

    Not in our library10.1158/0008-5472.can-10-2836

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