Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity

Radiation Oncology

Guangming Zhou¹  Nan Ding¹  Wentao Hu²  Libin Zhou¹  Lubomir B Smilenov³  Fengtao Su¹  Jufang Wang¹ 

[1] Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. China;Graduate School of Chinese Academy of Sciences, Beijing 100049, China;Center for Radiological Research, Columbia University Medical Center, New York, NY 10032, USA

关键词: genomic instability;    cell cycle checkpoint;    DNA damage;    tumorigenesis;    haploinsufficiency;    heterozygosity;   

Others  :  1223919
DOI  :  10.1186/1748-717X-6-96

 received in 2011-03-17, accepted in 2011-08-17,  发布年份 2011

【 摘 要 】

Background

Both epidemiological and experimental studies suggest that heterozygosity for a single gene is linked with tumorigenesis and heterozygosity for two genes increases the risk of tumor incidence. Our previous work has demonstrated that Atm/Brca1 double heterozygosity leads to higher cell transformation rate than single heterozygosity. However, the underlying mechanisms have not been fully understood yet. In the present study, a series of pathways were investigated to clarify the possible mechanisms of increased risk of tumorigenesis in Atm and Brca1 heterozygosity.

Methods

Wild type cells, Atm or Brca1 single heterozygous cells, and Atm/Brca1 double heterozygous cells were used to investigate DNA damage and repair, cell cycle, micronuclei, and cell transformation after photon irradiation.

Results

Remarkable high transformation frequency was confirmed in Atm/Brca1 double heterozygous cells compared to wild type cells. It was observed that delayed DNA damage recognition, disturbed cell cycle checkpoint, incomplete DNA repair, and increased genomic instability were involved in the biological networks. Haploinsufficiency of either ATM or BRCA1 negatively impacts these pathways.

Conclusions

The quantity of critical proteins such as ATM and BRCA1 plays an important role in determination of the fate of cells exposed to ionizing radiation and double heterozygosity increases the risk of tumorigenesis. These findings also benefit understanding of the individual susceptibility to tumor initiation.

【 授权许可】

   
2011 Wang et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Kwon CH, Zhao D, Chen J, Alcantara S, Li Y, Burns DK, Mason RP, Lee EY, Wu H, Parada LF: Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res 2008, 68:3286-3294.
• [2]Le Toriellec E, Despouy G, Pierron G, Gaye N, Joiner M, Bellanger D, Vincent-Salomon A, Stern MH: Haploinsufficiency of CDKN1B contributes to leukemogenesis in T-cell prolymphocytic leukemia. Blood 2008, 111:2321-2328.
• [3]Kucherlapati M, Yang K, Kuraguchi M, Zhao J, Lia M, Heyer J, Kane MF, Fan K, Russell R, Brown AM, Kneitz B, Edelmann W, Kolodner RD, Lipkin M, Kucherlapati R: Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression. Proc Natl Acad Sci USA 2002, 99:9924-9929.
• [4]Kleiman NJ, David J, Elliston CD, Hopkins KM, Smilenov LB, Brenner DJ, Worgul BV, Hall EJ, Lieberman HB: Mrad9 and atm haploinsufficiency enhance spontaneous and X-ray-induced cataractogenesis in mice. Radiat Res 2007, 168:567-573.
• [5]Izeradjene K, Combs C, Best M, Gopinathan A, Wagner A, Grady WM, Deng CX, Hruban RH, Adsay NV, Tuveson DA, Hingorani SR: Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 2007, 11:229-243.
• [6]Couto SS, Cao M, Duarte PC, Banach-Petrosky W, Wang S, Romanienko P, Wu H, Cardiff RD, Abate-Shen C, Cunha GR: Simultaneous haploinsufficiency of Pten and Trp53 tumor suppressor genes accelerates tumorigenesis in a mouse model of prostate cancer. Differentiation 2009, 77:103-111.
• [7]Umesako S, Fujisawa K, Iiga S, Mori N, Takahashi M, Hong DP, Song CW, Haga S, Imai S, Niwa O, Okumoto M: Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice. Breast Cancer Res 2005, 7:R164-170. BioMed Central Full Text
• [8]Bertout JA, Patel SA, Fryer BH, Durham AC, Covello KL, Olive KP, Goldschmidt MH, Simon MC: Heterozygosity for hypoxia inducible factor 1alpha decreases the incidence of thymic lymphomas in a p53 mutant mouse model. Cancer Res 2009, 69:3213-3220.
• [9]Barlow C, Eckhaus MA, Schaffer AA, Wynshaw-Boris A: Atm haploinsufficiency results in increased sensitivity to sublethal doses of ionizing radiation in mice. Nat Genet 1999, 21:359-360.
• [10]Bartek J, Lukas J, Bartkova J: DNA damage response as an anti-cancer barrier: damage threshold and the concept of 'conditional haploinsufficiency'. Cell Cycle 2007, 6:2344-2347.
• [11]Smilenov LB, Brenner DJ, Hall EJ: Modest increased sensitivity to radiation oncogenesis in ATM heterozygous versus wild-type mammalian cells. Cancer Res 2001, 61:5710-5713.
• [12]Bakkenist CJ, Kastan MB: DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 2003, 421:499-506.
• [13]Kozlov S, Gueven N, Keating K, Ramsay J, Lavin MF: ATP activates ataxia-telangiectasia mutated (ATM) in vitro. Importance of autophosphorylation. J Biol Chem 2003, 278:9309-9317.
• [14]Falck J, Mailand N, Syljuasen RG, Bartek J, Lukas J: The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 2001, 410:842-847.
• [15]Hall EJ, Worgul BV, Smilenov L, Elliston CD, Brenner DJ: The relative biological effectiveness of densely ionizing heavy-ion radiation for inducing ocular cataracts in wild type versus mice heterozygous for the ATM gene. Radiat Environ Biophys 2006, 45:99-104.
• [16]Worgul BV, Smilenov L, Brenner DJ, Junk A, Zhou W, Hall EJ: Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts. Proc Natl Acad Sci USA 2002, 99:9836-9839.
• [17]Lu S, Shen K, Wang Y, Santner SJ, Chen J, Brooks SC, Wang YA: Atm-haploinsufficiency enhances susceptibility to carcinogen-induced mammary tumors. Carcinogenesis 2006, 27:848-855.
• [18]Worgul BV, Smilenov L, Brenner DJ, Vazquez M, Hall EJ: Mice heterozygous for the ATM gene are more sensitive to both X-ray and heavy ion exposure than are wildtypes. Adv Space Res 2005, 35:254-259.
• [19]Yarden RI, Pardo-Reoyo S, Sgagias M, Cowan KH, Brody LC: BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nat Genet 2002, 30:285-289.
• [20]Powell SN, Kachnic LA: Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene 2003, 22:5784-5791.
• [21]Cousineau I, Belmaaza A: BRCA1 haploinsufficiency, but not heterozygosity for a BRCA1-truncating mutation, deregulates homologous recombination. Cell Cycle 2007, 6:962-971.
• [22]Latimer JJ, Rubinstein WS, Johnson JM, Kanbour-Shakir A, Vogel VG, Grant SG: Haploinsufficiency for BRCA1 is associated with normal levels of DNA nucleotide excision repair in breast tissue and blood lymphocytes. BMC Med Genet 2005, 6:26-37.
• [23]Jeng YM, Cai-Ng S, Li A, Furuta S, Chew H, Chen PL, Lee EY, Lee WH: Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation. Oncogene 2007, 26:6160-6166.
• [24]Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J: BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 2000, 14:927-939.
• [25]De la Torre C, Pincheira J, Lopez-Saez JF: Human syndromes with genomic instability and multiprotein machines that repair DNA double-strand breaks. Histol Histopathol 2003, 18:225-243.
• [26]Aglipay JA, Martin SA, Tawara H, Lee SW, Ouchi T: ATM activation by ionizing radiation requires BRCA1-associated BAAT1. J Biol Chem 2006, 281:9710-9718.
• [27]Gatei M, Scott SP, Filippovitch I, Soronika N, Lavin MF, Weber B, Khanna KK: Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Res 2000, 60:3299-3304.
• [28]Cortez D, Wang Y, Qin J, Elledge SJ: Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 1999, 286:1162-1166.
• [29]Xu B, Kim S, Kastan MB: Involvement of Brca1 in S-phase and G(2)-phase checkpoints after ionizing irradiation. Mol Cell Biol 2001, 21:3445-3450.
• [30]Tommiska J, Bartkova J, Heinonen M, Hautala L, Kilpivaara O, Eerola H, Aittomaki K, Hofstetter B, Lukas J, von Smitten K, Blomqvist C, Ristimaki A, Heikkila P, Bartek J, Nevanlinna H: The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer. Oncogene 2008, 27:2501-2506.
• [31]Andrieu N, Cavaciuti E, Lauge A, Ossian K, Hall J, Stoppa-Lyonnet D: Ataxia-telangiectasia genes and breast cancer risk in a French family study. J Dairy Res 2005, 72:Spec No: 73-80.
• [32]FitzGerald MG, Bean JM, Hegde SR, Unsal H, MacDonald DJ, Harkin DP, Finkelstein DM, Isselbacher KJ, Haber DA: Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 1997, 15:307-310.
• [33]Geoffroy-Perez B, Janin N, Ossian K, Lauge A, Croquette MF, Griscelli C, Debre M, Bressac-de-Paillerets B, Aurias A, Stoppa-Lyonnet D, Andrieu N: Cancer risk in heterozygotes for ataxia-telangiectasia. Int J Cancer 2001, 93:288-293.
• [34]Swift M, Lukin JL: Breast cancer incidence and the effect of cigarette smoking in heterozygous carriers of mutations in the ataxia-telangiectasia gene. Cancer Epidemiol Biomarkers Prev 2008, 17:3188-3192.
• [35]Bowen TJ, Yakushiji H, Montagna C, Jain S, Ried T, Wynshaw-Boris A: Atm heterozygosity cooperates with loss of Brca1 to increase the severity of mammary gland cancer and reduce ductal branching. Cancer Res 2005, 65:8736-8746.
• [36]Su F, Smilenov LB, Ludwig T, Zhou L, Zhu J, Zhou G, Hall EJ: Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis. Radiat Oncol 2010, 5:15-23. BioMed Central Full Text
• [37]Zhou G, Bennett PV, Cutter NC, Sutherland BM: Proton-HZE-particle sequential dual-beam exposures increase anchorage-independent growth frequencies in primary human fibroblasts. Radiat Res 2006, 166:488-494.
• [38]Olive PL, Wlodek D, Durand RE, Banath JP: Factors influencing DNA migration from individual cells subjected to gel electrophoresis. Exp Cell Res 1992, 198:259-267.
• [39]Konca K, Lankoff A, Banasik A, Lisowska H, Kuszewski T, Gozdz S, Koza Z, Wojcik A: A cross-platform public domain PC image-analysis program for the comet assay. Mutat Res 2003, 534:15-20.
• [40]Zhou G, Kawata T, Furusawa Y, Aoki M, Hirayama R, Ando K, Ito H: Protective effects of melatonin against low- and high-LET irradiation. J Radiat Res 2006, 47:175-181.
• [41]Sedelnikova OA, Rogakou EP, Panyutin IG, Bonner WM: Quantitative detection of (125)IdU-induced DNA double-strand breaks with gamma-H2AX antibody. Radiat Res 2002, 158:486-492.
• [42]Smilenov LB, Tumor development: Haploinsufficiency and local network assembly. Cancer Lett 2006, 240:17-28.
• [43]Rogakou EP, Boon C, Redon C, Bonner WM: Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 1999, 146:905-916.
• [44]Pilch DR, Sedelnikova OA, Redon C, Celeste A, Nussenzweig A, Bonner WM: Characteristics of gamma-H2AX foci at DNA double-strand breaks sites. Biochem Cell Biol 2003, 81:123-129.
• [45]Buscemi G, Perego P, Carenini N, Nakanishi M, Chessa L, Chen J, Khanna K, Delia D: Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks. Oncogene 2004, 23:7691-7700.
• [46]Kastan MB, Lim DS: The many substrates and functions of ATM. Nat Rev Mol Cell Biol 2000, 1:179-186.
• [47]Smilenov LB, Lieberman HB, Mitchell SA, Baker RA, Hopkins KM, Hall EJ: Combined haploinsufficiency for ATM and RAD9 as a factor in cell transformation, apoptosis, and DNA lesion repair dynamics. Cancer Res 2005, 65:933-938.
• [48]Nieuwenhuis B, Van Assen-Bolt AJ, Van Waarde-Verhagen MA, Sijmons RH, Van der Hout AH, Bauch T, Streffer C, Kampinga HH: BRCA1 and BRCA2 heterozygosity and repair of X-ray-induced DNA damage. Int J Radiat Biol 2002, 78:285-295.