Oxygen sensing and the DNA-damage response

Current Opinion in Cell Biology

Volumn 19, Issue 6, 2007, Pages 680-684

  Hammond, Ester M ^a   Kaufmann, Muriel R ^b   Giaccia, Amato J ^b  

^a CHURCHILL HOSPITAL   (United Kingdom)

^b STANFORD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ATM PROTEIN; CHECKPOINT KINASE 2; CHECKPOINT KINASE RAD3; DNA; HYPOXIA INDUCIBLE FACTOR 1; HYPOXIA INDUCIBLE FACTOR 1ALPHA; PROCOLLAGEN PROLINE 2 OXOGLUTARATE 4 DIOXYGENASE; VON HIPPEL LINDAU PROTEIN;

DNA DAMAGE; DNA REPAIR; HOMOLOGOUS RECOMBINATION; HUMAN; HYPOXIA; OXYGEN SENSING; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REOXYGENATION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; DNA DAMAGE; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1; OXIDATIVE STRESS; OXYGEN; REACTIVE OXYGEN SPECIES;

EID: 36749001007     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ceb.2007.10.002     Document Type: Review

References (36)

1. Nordsmark M., Overgaard M., and Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 41 (1996) 31-39. This report shows a correlation between oxygenation status and radiation response in advanced squamous cell carcinoma of head and neck.
2. Nordsmark M., Bentzen S.M., Rudat V., Brizel D., Lartigau E., Stadler P., Becker A., Adam M., Molls M., Dunst J., et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 77 (2005) 18-24
3. Hockel M., Schlenger K., Aral B., Mitze M., Schaffer U., and Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56 (1996) 4509-4515. This report validates a study of 103 patients with advanced cancers of the uterine cervix in which tumor oxygenation was measured using a computerized polarographic electrode system. Hypoxic tumors were found to be larger and showed more frequent parametrical spread compared to nonhypoxic tumors. Patients with hypoxic tumors had significantly worse survival probabilities than patients with well-oxygenated tumors.
4. Brizel D.M., Sibley G.S., Prosnitz L.R., Scher R.L., and Dewhirst M.W. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 38 (1997) 285-289
5. Fyles A.W., Milosevic M., Wong R., Kavanagh M.C., Pintilie M., Sun A., Chapman W., Levin W., Manchul L., Keane T.J., et al. Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol 50 (1998) 149-156. All these studies show a strong association between tumor hypoxia and poor patient's prognosis independently of other prognostic variables.
6. Vaupel P., Mayer A., and Hockel M. Tumor hypoxia and malignant progression. Methods Enzymol 381 (2004) 335-354
7. Brown J.M., and Wilson W.R. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4 (2004) 437-447. This review discusses the possibility to exploit tumor hypoxia for tumor selective therapy, including prodrugs activated by hypoxia, hypoxia-specific gene therapy, targeting the hypoxia-inducible factor 1 transcription factor, and recombinant anaerobic bacteria.
8. Brown J.M., and Giaccia A.J. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 58 (1998) 1408-1416. This review reports how hypoxia-selective cytotoxins take advantage of the unique low oxygen tension in the majority of human solid tumors. It discusses how the tumor microenvironment is a stimulus to angiogenesis and how inhibition of angiogenesis and the use of gene therapy can be a powerful method of anticancer therapy.
9. Zhou B.B., and Elledge S.J. The DNA damage response: putting checkpoints in perspective. Nature 408 (2000) 433-439
10. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3 (2003) 155-168. This review extensively describes the role of ATM and related kinases in the DNA-damage response and discusses the association between defective DNA-damage response pathways and cancer.
11. Shiomi Y., Shinozaki A., Nakada D., Sugimoto K., Usukura J., Obuse C., and Tsurimoto T. Clamp and clamp loader structures of the human checkpoint protein complexes, Rad9-1-1 and Rad17-RFC. Genes Cells 7 (2002) 861-868
12. Stewart G.S., Wang B., Bignell C.R., Taylor A.M., and Elledge S.J. MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421 (2003) 961-966. This was the first report showing that MDC1 together with H2AX works to promote recruitment of repair proteins to the sites of DNA strand breaks. MDC1 forms foci that colocalize with γ-H2AX-foci and this foci formation is dependent on H2AX. Cells lacking MDC1 are sensitive to IR and fail to activate S-phase and G2/M-phase arrest after exposure to IR going together with their inability to properly regulate Chk1.
13. Kastan M.B., and Lim D.S. The many substrates and functions of ATM. Nat Rev Mol Cell Biol 1 (2000) 179-186
14. Bartkova J., Horejsi Z., Koed K., Kramer A., Tort F., Zieger K., Guldberg P., Sehested M., Nesland J.M., Lukas C., et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434 (2005) 864-870. This report describes the expression of markers of an activated DNA-damage response such as ATM, Chk2, H2AX, and p53 in different human tumor samples. It is suggested that ATM/ATR-regulated DNA-damage response pathways are activated early in tumorigenesis and that this delays or prevents cancer. Mutations comprising this pathway are proposed to allow cell proliferation, survival, increased genomic instability, and tumor progression.
15. Gorgoulis V.G., Vassiliou L.V., Karakaidos P., Zacharatos P., Kotsinas A., Liloglou T., Venere M., Ditullio Jr. R.A., Kastrinakis N.G., Levy B., et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434 (2005) 907-913. A range of human lung hyperplasias were analyzed in this report. Markers of an activated DNA-damage response, including H2AX and Chk2 phosphorylation, focal staining of 53BP1, and apoptosis were found. These and other findings indicate that cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability, and selective pressure for p53 mutations.
16. 2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15 (1999) 551-578
17. Maxwell P.H., Wiesener M.S., Chang G.W., Clifford S.C., Vaux E.C., Cockman M.E., Wykoff C.C., Pugh C.W., Maher E.R., and Ratcliffe P.J. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399 (1999) 271-275. This was the first report demonstrating that HIF-α subunits are constitutively stabilized in VHL-deficient cells and that its reintroduction restored oxygen-dependent instability.
18. Hammond E.M., Denko N.C., Dorie M.J., Abraham R.T., and Giaccia A.J. Hypoxia links ATR and p53 through replication arrest. Mol Cell Biol 22 (2002) 1834-1843. This was the first report showing that ATR responds to severe hypoxia by phosphorylating both p53 and Chk1. This ATR activity only occurs at oxygen concentrations low enough to induce a replication arrest and occur in S-phase cells in the absence of detectable DNA damage.
19. To K.K.-W., Sedelnikova O.A., Samons M., Bonner W.M., and Huang L.E. The phosphorylation status of PAS-B distinguishes HIF-1a from HIF-2a in NBS1 repression. EMBO J 25 (2006) 4784-4794. This was the first report showing that PAS-B of HIF-1α but not of HIF-2α induces DNA double-strand breaks at least in part by repressing the expression of NBS1 and gives it a unique role in tumor progression by promoting genomic instability.
20. Huang L.E., Bindra R.S., Glazer P.M., and Harris A.L. Hypoxia-induced genetic instability - a calculated mechanism underlying tumor progression. J Mol Med 85 (2007) 139-148. This review summarizes the recent findings about how hypoxia functionally impairs various DNA repair pathways resulting in genetic instability and their implications in tumor progression and treatment.
21. Mihaylova V.T., Bindra R.S., Yuan J., Campisi D., Narayanan L., Jensen R., Giordano F., Johnson R.S., Rockwell S., and Galazer P.M. Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mol Cell Biol 6 (2003) 23
22. Koshiji M., To K.K.-W., Hammer S., Kumamoto K., Harris A.L., Modrich P., and Huang L.E. HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Mol Cell 17 6 (2005) 793-803. This was the fist report showing that genetic instability under hypoxia is induced by downregulation of MSH2 and MSH6. Furthermore, it is shown that HIF-1a is associated with the loss of MSH2 expression which indicates that the regulation of DNA repair is an integral part of the hypoxic response.
23. Yuan J., Narayanan L., Rockwell S., and Glazer P.M. Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH. Cancer Res 60 (2000) 4372-4376
24. Meng A.X., Jalali F., Cuddihy A., Chan N., Bindra R.S., Glazer P.M., and Bristow R.G. Hypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells. Radiother Oncol 76 (2005) 168-176. This report shows the downregulation of many genes involved in HR such as Rad51, Rad52, Rad54, BRCA1, and BRCA2 on the RNA level both in normal and cancer cells. Decrease in RNA of NHEJ genes was observed.
25. Bindra R.S., Schaffer P.J., Meng A., Woo J., Maseide K., Roth M.E., Lizardi P., Hedley D.W., Bristow R.G., and Glazer P.M. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol 24 (2004) 8504-8518. This article reports the downregulation of Rad51 in response to hypoxia that is neither cell cycle nor HIF-1-dependent. Simultaneously, homologous recombination was found to be reduced which suggests that the downregulation of Rad51 under hypoxia has functional consequences for DNA repair.
26. Hammond E.M., Green S.L., and Giaccia A.J. Comparison of hypoxia-induced replication arrest with hydroxyurea and aphidicolin-induced arrest. Mutat Res 532 (2003) 205-213. This paper reports that severe hypoxia induces a rapid S-phase arrest, which is independent of p53, p21, and HIF-1. The arrest does not result from a lack of available dNTPs.
27. Hammond E.M., Dorie M.J., and Giaccia A.J. Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation. Cancer Res 64 (2004) 6556-6562. This paper reports that replication arrest during hypoxia leads to the accumulation of regions of single-stranded DNA, which are proposed to be detected by ATR/ATRIP/RPA. Inhibition of ATR leads to the collapse of stalled replication forks and the accumulation of DNA damage. Inhibition of both ATR and Chk1 increases sensitivity to hypoxia/reoxygenation.
28. Lopes M., Cotta-Ramusino C., Pellicioli A., Liberi G., Plevani P., Muzi-Falconi M., Newlon C.S., and Foiani M. The DNA replication checkpoint response stabilizes stalled replication forks. Nature 412 (2001) 557-561. This was the first report showing the requirement of Rad53 to properly maintain stable replication forks during the block. Hydroxyurea-treated rad53 mutants accumulate unusual DNA structures at replication forks that correlate with the inability to dephosphorylate Rad53.
29. Cimprich K.A. Fragile sites: breaking up over a slowdown. Curr Biol 13 (2003) R231-R233. This paper reports that fragile sites in the human genome that are prone to genomic instability under replicative stress depend on ATR to maintain their stability.
30. Hammond E.M., Dorie M.J., and Giaccia A.J. ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. J Biol Chem 278 (2003) 12207-12213. This paper reports that during reoxygenation the ATM kinase is responsible for maintaining the phosphorylation of hypoxia-stabilized p53.
31. Freiberg R.A., Hammond E.M., Dorie M.J., Welford S.M., and Giaccia A.J. DNA damage during reoxygenation elicits a Chk2-dependent checkpoint response. Mol Cell Biol 26 (2006) 1598-1609. This paper reports that hypoxia/reoxygenation induces a G2 arrest which is dependent on signaling from ATM through Chk2 and cdc2/cdc25C. Inhibition of this pathway sensitizes cells to hypoxia/reoxygenation.
32. Bakkenist C.J., and Kastan M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421 (2003) 499-506. This was the first report suggesting that ATM is activated upon DNA damage by rapid intermolecular phosphorylation on serine 1981 that leads to dimer dissociation and activation of the ATM kinase. It shows that ATM is hold inactive as a dimer with the kinase domain bound to a region surrounding serine 1981 that is contained in the previously described FAT-domain.
33. Gibson S.L., Bindra R.S., and Glazer P.M. Hypoxia-induced phosphorylation of Chk2 in an ataxia telangiectasia mutated-dependent manner. Cancer Res 65 (2005) 10734-10741
34. Uziel T., Lerenthal Y., Moyal L., Andegeko Y., Mittelman L., and Shiloh Y. Requirement of the MRN complex for ATM activation by DNA damage. EMBO J 22 (2003) 5612-5621
35. Stiff T., Walker S.A., Cerosaletti K., Goodarzi A.A., Petermann E., Concannon P., O'Driscoll M., and Jeggo P.A. ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling. EMBO J 25 (2006) 5775-5782. This was the first report showing that ATM activation upon UV treatment or replication fork stalling is dependent on ATR but independent of ATM.
36. Freiberg R.A., Krieg A.J., Giaccia A.J., and Hammond E.M. Checking in on hypoxia/reoxygenation. Cell Cycle 5 (2006) 1304-1307