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系統識別號 U0026-1502201112014500
論文名稱(中文) α-Catulin在癌細胞的衰老扮演重要角色
論文名稱(英文) α-Catulin plays an important role in senescence of cancer cells
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 99
學期 1
出版年 100
研究生(中文) 范麗卿
研究生(英文) Li-Ching Fan
學號 S5894152
學位類別 博士
語文別 英文
論文頁數 105頁
口試委員 口試委員-張俊彥
口試委員-陳健尉
口試委員-劉校生
召集委員-張文粲
口試委員-洪澤民
指導教授-陳玉玲
中文關鍵字 α-catulin  衰老  p53  去氧核醣核苷酸傷害  cDNA微晶片  癌症 
英文關鍵字 α-catulin  senescence  p53  DNA damage  cDNA microarray  cancer 
學科別分類
中文摘要 細胞衰老可保護抵抗癌進程而有腫瘤抑癌的功能。α-Catulin是一個與α-catenin相近似的蛋白質,並且因其可調控NF-B路徑而被報導有造成腫瘤生成的潛在能力,但是它的臨床相關性和調控癌進程的機轉是少被知道的。本研究發現在癌細胞株和臨床口腔鱗狀細胞癌 (簡稱OSCC) 的α-catulin mRNA的高量表現是具有統計意義的,α-catulin的表現量與腫瘤大小 (P值等於0.001) 和AJCC stage (P值等於0.004) 是呈現正相關性的。在OC2口腔癌細胞株和A549肺癌細胞株內抑制α-catulin的表現量可強烈地抑制細胞增生,誘導造成細胞的提前型衰老和抑制OC2癌細胞異種移植的腫瘤生長。機轉性的分析結果顯示在癌細胞內抑制α-catulin的表現量可強烈地誘導造成去氧核醣核苷酸傷害反應 (簡稱DDR),並且在A549細胞內是經由p53/p21-依賴型路徑,但是在帶有突變型p53的OC2細胞內則是經由p53/p21-非依賴型路徑。利用cDNA微晶片技術進一步探討在OC2細胞內抑制α-catulin所誘導造成的提前型衰老,結果顯示細胞週期調控和去氧核醣核苷酸傷害反應路徑的改變在前衰老階段是最有統計意義的,並且發現好幾個關於有絲分裂染色體濃縮,去氧核醣核苷酸傷害反應和去氧核醣核苷酸修複系統的基因是具有統計意義地受到負調控。這些結果也說明在OC2細胞內抑制α-catulin所誘導造成的提前型衰老可能是初期受到染色體濃縮失敗,嚴重的去氧核醣核苷酸傷害和受損的去氧核醣核苷酸修複能力所造成的。本研究不僅發現抑制α-catulin可誘導造成癌細胞的提前型衰老,同時也發現在人類正常口腔角質細胞 (簡稱 NHOK) 和人類齒齦纖維母細胞 (簡稱 HGF) 內的α-catulin表現量會伴隨著複製型衰老的過程而逐漸減少,說明α-catulin的表現量和複製型衰老的關係是呈現負關聯性的。更進一步在代數早期的人類齒齦纖維母細胞 (第十代) 內過度表達α-catulin 可明顯延遲衰老的發生和促進移行。相反地,抑制α-catulin的表現可誘導造成人類齒齦纖維母細胞的提前型衰老。整體而言,本研究是首先提出證據說明α-catulin可能有致癌基因的功能:抑制α-catulin可明顯阻止腫瘤的生長和誘導造成癌細胞的提前型衰老;α-catulin在正常細胞的過度表達可明顯延遲衰老和促進移行。這些結果也指出α-catulin是一個抗老化基因且其過度表現對癌進程是重要的。因此,了解α-catulin的功能與其調控對於癌症醫療或許是一種有希望的治療方式。
英文摘要 Cellular senescence functions as a tumor suppressor that protects against cancer progression. α-Catulin, an α-catenin-related protein, is reported to have tumorigenic potential because it regulates the NF-B pathway, but little is known about its clinical relevance and the mechanism through which it regulates cancer progression. Here, we found that α-catulin mRNA levels were significantly upregulated in cancer cell lines and clinical oral squamous cell carcinomas (OSCC), which positively correlated with tumor size (P = 0.001) and AJCC stage (P = 0.004). α-Catulin knockdown in the oral cancer cell line, OC2 and lung cancer cell line, A549 dramatically decreased cell proliferation and contributed to premature senescence, and inhibited OC2 xenograft growth. Mechanistic dissection showed that α-catulin depletion strongly induced the DNA damage response (DDR) in both cell lines, via a p53/p21-dependent pathway in A549 cells, but a p53/p21-independent pathway in OC2 cells carrying mutant p53. Further investigating the mechanisms by which α-catulin-knockdown-induced premature senescence in OC2 cells using cDNA microarray technique revealed that cell cycle regulation and DDR pathways were the top two pathways significantly altered at the presenescent stage as well as significantly downregulated several crucial genes related to mitotic chromosome condensation, DDR, and DNA repair systems. These results suggested that α-catulin-knockdown-induced premature senescence in OC2 cells may initially caused by chromosome condensation failures, severe DNA damage, and impaired DNA repair ability. In addition to the effect of α-catulin-knockdown-induced premature senescence in cancer cells, our results also showed that the expression of α-catulin was gradually decreased in the process of replicative senescence in human normal oral keratinocytes (NHOK) and human gingival fibroblast (HGF) cells, suggesting that the negative relationship between α-catulin expression and replicative senescence. Further overexpressing of α-catulin in early passage HGF (10th passage) cells apparently delayed the occurrence of senescence and promoted the migration. Conversely, its depletion induced premature senescence in HGF cells. Collectively, our study provides the first evidence that α-catulin may function as an oncogene: its knockdown significantly inhibited tumor growth and induced premature senescence in cancer cells; however, its overexpression apparently delayed the senescence and promoted the migration in normal cells. These results also indicated α-catulin is an anti-aging gene and its overexpression is crucial for tumor progression. Thus, understanding of α-catulin function and regulation may be a promising therapeutic approach for cancer treatment.
論文目次 Abstract…………………………………………… 1
Chinese ……………………………………… 1
English………………………………………… 2
Acknowledgments………………………… 3
Contents…………………………………………… 4
Abbreviation…………………………………… 11
Introduction…………………………………… 13
Specific Aims………………………………… 21
Materials and Methods…………… 22
Results……………………………………………… 33
Discussion…………………………………………… 44
Conclusion and Prospect………… 53
References…………………………………………… 56
Tables……………………………………………………… 66
Figures…………………………………………………… 69
Autobiography…………………………………… 104
Publications……………………………………… 105
參考文獻 Aberle H, Schwartz H, Kemler R (1996). Cadherin-catenin complex: protein interactions and their implications for cadherin function. J Cell Biochem 61: 514-23.
Aliouat-Denis CM, Dendouga N, Van den Wyngaert I, Goehlmann H, Steller U, van de Weyer I et al (2005). p53-independent regulation of p21Waf1/Cip1 expression and senescence by Chk2. Mol Cancer Res 3: 627-34.
Arnaudeau C, Lundin C, Helleday T (2001). DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells. J Mol Biol 307: 1235-45.
Barth AI, Nathke IS, Nelson WJ (1997). Cadherins, catenins and APC protein: interplay between cytoskeletal complexes and signaling pathways. Curr Opin Cell Biol 9: 683-90.
Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K et al (2005). DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434: 864-70.
Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N et al (2006). Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444: 633-7.
Bassing CH, Chua KF, Sekiguchi J, Suh H, Whitlow SR, Fleming JC et al (2002). Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX. Proc Natl Acad Sci U S A 99: 8173-8.
Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, Eckersdorff M et al (2003). Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114: 359-70.
Bear MD, Li M, Liu Y, Giel-Moloney MA, Fanburg BL, Toksoz D (2010). The Lbc Rho guanine nucleotide exchange factor/{alpha} -catulin axis functions in serotonin-induced vascular smooth muscle cell mitogenesis and RhoA/ROCK activation. J Biol Chem 285: 32919-26.
Bekker-Jensen S, Lukas C, Kitagawa R, Melander F, Kastan MB, Bartek J et al (2006). Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks. J Cell Biol 173: 195-206.
Blasco MA (2005). Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6: 611-22.
Bond JA, Wyllie FS, Wynford-Thomas D (1994). Escape from senescence in human diploid fibroblasts induced directly by mutant p53. Oncogene 9: 1885-9.
Brown JP, Wei W, Sedivy JM (1997). Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277: 831-4.
Bullions LC, Notterman DA, Chung LS, Levine AJ (1997). Expression of wild-type alpha-catenin protein in cells with a mutant alpha-catenin gene restores both growth regulation and tumor suppressor activities. Mol Cell Biol 17: 4501-8.
Buscemi G, Perego P, Carenini N, Nakanishi M, Chessa L, Chen J et al (2004). Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks. Oncogene 23: 7691-700.
Caino MC, Meshki J, Kazanietz MG (2009). Hallmarks for senescence in carcinogenesis: novel signaling players. Apoptosis 14: 392-408.
Campisi J, d'Adda di Fagagna F (2007). Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8: 729-40.
Carmena M, Earnshaw WC (2003). The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 4: 842-54.
Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA et al (2002). Genomic instability in mice lacking histone H2AX. Science 296: 922-7.
Chang BD, Broude EV, Dokmanovic M, Zhu H, Ruth A, Xuan Y et al (1999a). A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res 59: 3761-7.
Chang BD, Xuan Y, Broude EV, Zhu H, Schott B, Fang J et al (1999b). Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs. Oncogene 18: 4808-18.
Chen QM, Bartholomew JC, Campisi J, Acosta M, Reagan JD, Ames BN (1998). Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication. Biochem J 332 ( Pt 1): 43-50.
Chen Y, Chen PL, Chen CF, Jiang X, Riley DJ (2008). Never-in-mitosis related kinase 1 functions in DNA damage response and checkpoint control. Cell Cycle 7: 3194-201.
Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M et al (2005). Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436: 725-30.
Christoffersen NR, Shalgi R, Frankel LB, Leucci E, Lees M, Klausen M et al (2009). p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death Differ.
Coelho PA, Queiroz-Machado J, Sunkel CE (2003). Condensin-dependent localisation of topoisomerase II to an axial chromosomal structure is required for sister chromatid resolution during mitosis. J Cell Sci 116: 4763-76.
Coleman ML, Marshall CJ, Olson MF (2004). RAS and RHO GTPases in G1-phase cell-cycle regulation. Nat Rev Mol Cell Biol 5: 355-66.
Collado M, Blasco MA, Serrano M (2007). Cellular senescence in cancer and aging. Cell 130: 223-33.
Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M et al (2005). Tumour biology: senescence in premalignant tumours. Nature 436: 642.
Crosio C, Fimia GM, Loury R, Kimura M, Okano Y, Zhou H et al (2002). Mitotic phosphorylation of histone H3: spatio-temporal regulation by mammalian Aurora kinases. Mol Cell Biol 22: 874-85.
d'Adda di Fagagna F (2008). Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8: 512-22.
d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T et al (2003). A DNA damage checkpoint response in telomere-initiated senescence. Nature 426: 194-8.
de Lange T (2002). Protection of mammalian telomeres. Oncogene 21: 532-40.
de Lange T, Shiue L, Myers RM, Cox DR, Naylor SL, Killery AM et al (1990). Structure and variability of human chromosome ends. Mol Cell Biol 10: 518-27.
de Vries A, Flores ER, Miranda B, Hsieh HM, van Oostrom CT, Sage J et al (2002). Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function. Proc Natl Acad Sci U S A 99: 2948-53.
Deng C, Zhang P, Harper JW, Elledge SJ, Leder P (1995). Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82: 675-84.
Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C et al (2006). Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444: 638-42.
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C et al (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92: 9363-7.
Dolado I, Swat A, Ajenjo N, De Vita G, Cuadrado A, Nebreda AR (2007). p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer Cell 11: 191-205.
Downs JA, Nussenzweig MC, Nussenzweig A (2007). Chromatin dynamics and the preservation of genetic information. Nature 447: 951-958.
Frippiat C, Chen QM, Remacle J, Toussaint O (2000). Cell cycle regulation in H(2)O(2)-induced premature senescence of human diploid fibroblasts and regulatory control exerted by the papilloma virus E6 and E7 proteins. Exp Gerontol 35: 733-45.
Giannini AL, Vivanco MM, Kypta RM (2000). Analysis of beta-catenin aggregation and localization using GFP fusion proteins: nuclear import of alpha-catenin by the beta-catenin/Tcf complex. Exp Cell Res 255: 207-20.
Gire V, Roux P, Wynford-Thomas D, Brondello JM, Dulic V (2004). DNA damage checkpoint kinase Chk2 triggers replicative senescence. Embo J 23: 2554-63.
Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T et al (2005). Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434: 907-13.
Ha L, Ichikawa T, Anver M, Dickins R, Lowe S, Sharpless NE et al (2007). ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence. Proc Natl Acad Sci U S A 104: 10968-73.
Hakem R (2008). DNA-damage repair; the good, the bad, and the ugly. Embo J 27: 589-605.
Harley CB, Futcher AB, Greider CW (1990). Telomeres shorten during ageing of human fibroblasts. Nature 345: 458-60.
Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC (1990). Telomere reduction in human colorectal carcinoma and with ageing. Nature 346: 866-8.
Hayflick L, Moorhead PS (1961). The serial cultivation of human diploid cell strains. Exp Cell Res 25: 585-621.
Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA (2008). DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8: 193-204.
Hemann MT, Narita M (2007). Oncogenes and senescence: breaking down in the fast lane. Genes Dev 21: 1-5.
Hemann MT, Strong MA, Hao LY, Greider CW (2001). The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107: 67-77.
Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM (2004). Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell 14: 501-13.
Hsiang YH, Lihou MG, Liu LF (1989). Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49: 5077-82.
Huang JC, Svoboda DL, Reardon JT, Sancar A (1992). Human nucleotide excision nuclease removes thymine dimers from DNA by incising the 22nd phosphodiester bond 5' and the 6th phosphodiester bond 3' to the photodimer. Proc Natl Acad Sci U S A 89: 3664-8.
Huck JJ, Zhang M, McDonald A, Bowman D, Hoar KM, Stringer B et al (2010). MLN8054, an Inhibitor of Aurora A Kinase, Induces Senescence in Human Tumor Cells Both In vitro and In vivo. Mol Cancer Res 8: 373-84.
Hudson DF, Marshall KM, Earnshaw WC (2009). Condensin: Architect of mitotic chromosomes. Chromosome Res 17: 131-44.
Janssens B, Staes K, van Roy F (1999). Human alpha-catulin, a novel alpha-catenin-like molecule with conserved genomic structure, but deviating alternative splicing. Biochim Biophys Acta 1447: 341-7.
Jeggo PA, Lobrich M (2007). DNA double-strand breaks: their cellular and clinical impact? Oncogene 26: 7717-9.
Kielbassa C, Roza L, Epe B (1997). Wavelength dependence of oxidative DNA damage induced by UV and visible light. Carcinogenesis 18: 811-6.
Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL et al (1994). Specific association of human telomerase activity with immortal cells and cancer. Science 266: 2011-5.
Kunkel TA, Erie DA (2005). DNA mismatch repair. Annu Rev Biochem 74: 681-710.
Lam AK, Ong K, Ho YH (2008). Aurora kinase expression in colorectal adenocarcinoma: correlations with clinicopathological features, p16 expression, and telomerase activity. Hum Pathol 39: 599-604.
Lee AC, Fenster BE, Ito H, Takeda K, Bae NS, Hirai T et al (1999). Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J Biol Chem 274: 7936-40.
Li JJ, Weroha SJ, Lingle WL, Papa D, Salisbury JL, Li SA (2004). Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats. Proc Natl Acad Sci U S A 101: 18123-8.
Li W, Ge Z, Liu C, Liu Z, Bjorkholm M, Jia J et al (2008). CIP2A is overexpressed in gastric cancer and its depletion leads to impaired clonogenicity, senescence, or differentiation of tumor cells. Clin Cancer Res 14: 3722-8.
Li Y, Qian H, Li X, Wang H, Yu J, Liu Y et al (2009). Adenoviral-mediated gene transfer of Gadd45a results in suppression by inducing apoptosis and cell cycle arrest in pancreatic cancer cell. J Gene Med 11: 3-13.
Lindsey J, McGill NI, Lindsey LA, Green DK, Cooke HJ (1991). In vivo loss of telomeric repeats with age in humans. Mutat Res 256: 45-8.
Liu Y, Tseng M, Perdreau SA, Rossi F, Antonescu C, Besmer P et al (2007). Histone H2AX is a mediator of gastrointestinal stromal tumor cell apoptosis following treatment with imatinib mesylate. Cancer Res 67: 2685-92.
Lleonart ME, Artero-Castro A, Kondoh H (2009). Senescence induction; a possible cancer therapy. Mol Cancer 8: 3.
MacLaren A, Black EJ, Clark W, Gillespie DA (2004). c-Jun-deficient cells undergo premature senescence as a result of spontaneous DNA damage accumulation. Mol Cell Biol 24: 9006-18.
Mallette FA, Gaumont-Leclerc MF, Ferbeyre G (2007). The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev 21: 43-8.
Markovits J, Pommier Y, Kerrigan D, Covey JM, Tilchen EJ, Kohn KW (1987). Topoisomerase II-mediated DNA breaks and cytotoxicity in relation to cell proliferation and the cell cycle in NIH 3T3 fibroblasts and L1210 leukemia cells. Cancer Res 47: 2050-5.
McKinnon PJ, Caldecott KW (2007). DNA strand break repair and human genetic disease. Annu Rev Genomics Hum Genet 8: 37-55.
Merdek KD, Nguyen NT, Toksoz D (2004). Distinct activities of the alpha-catenin family, alpha-catulin and alpha-catenin, on beta-catenin-mediated signaling. Mol Cell Biol 24: 2410-22.
Mikhailov A, Cole RW, Rieder CL (2002). DNA damage during mitosis in human cells delays the metaphase/anaphase transition via the spindle-assembly checkpoint. Curr Biol 12: 1797-806.
Miura K, Suzuki K, Tokino T, Isomura M, Inazawa J, Matsuno S et al (1996). Detailed deletion mapping in squamous cell carcinomas of the esophagus narrows a region containing a putative tumor suppressor gene to about 200 kilobases on distal chromosome 9q. Cancer Res 56: 1629-34.
Murr R, Loizou JI, Yang YG, Cuenin C, Li H, Wang ZQ et al (2006). Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nat Cell Biol 8: 91-9.
Narita M, Nuñez S, Heard E, Narita M, Lin AW, Hearn SA et al (2003). Rb-Mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence. Cell 113: 703-716.
Novik KL, Spinelli JJ, Macarthur AC, Shumansky K, Sipahimalani P, Leach S et al (2007). Genetic variation in H2AFX contributes to risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 16: 1098-106.
Nowosielska A, Marinus MG (2008). DNA mismatch repair-induced double-strand breaks. DNA Repair (Amst) 7: 48-56.
O'Connell MJ, Krien MJ, Hunter T (2003). Never say never. The NIMA-related protein kinases in mitotic control. Trends Cell Biol 13: 221-8.
Olovnikov AM (1973). A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 41: 181-90.
Ouchi M, Fujiuchi N, Sasai K, Katayama H, Minamishima YA, Ongusaha PP et al (2004). BRCA1 phosphorylation by Aurora-A in the regulation of G2 to M transition. J Biol Chem 279: 19643-8.
Parikh RA, White JS, Huang X, Schoppy DW, Baysal BE, Baskaran R et al (2007). Loss of distal 11q is associated with DNA repair deficiency and reduced sensitivity to ionizing radiation in head and neck squamous cell carcinoma. Genes Chromosomes Cancer 46: 761-75.
Park B, Nguyen NT, Dutt P, Merdek KD, Bashar M, Sterpetti P et al (2002). Association of Lbc Rho guanine nucleotide exchange factor with alpha-catenin-related protein, alpha-catulin/CTNNAL1, supports serum response factor activation. J Biol Chem 277: 45361-70.
Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J (2003). Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 5: 741-7.
Pastink A, Eeken JC, Lohman PH (2001). Genomic integrity and the repair of double-strand DNA breaks. Mutat Res 480-481: 37-50.
Rattner JB, Hendzel MJ, Furbee CS, Muller MT, Bazett-Jones DP (1996). Topoisomerase II alpha is associated with the mammalian centromere in a cell cycle- and species-specific manner and is required for proper centromere/kinetochore structure. J Cell Biol 134: 1097-107.
Ray S, Atkuri KR, Deb-Basu D, Adler AS, Chang HY, Herzenberg LA et al (2006). MYC can induce DNA breaks in vivo and in vitro independent of reactive oxygen species. Cancer Res 66: 6598-605.
Rogakou EP, Boon C, Redon C, Bonner WM (1999). Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 146: 905-16.
Rosemary Siafakas A, Richardson DR (2009). Growth arrest and DNA damage-45 alpha (GADD45alpha). Int J Biochem Cell Biol 41: 986-9.
Sargent RG, Brenneman MA, Wilson JH (1997). Repair of site-specific double-strand breaks in a mammalian chromosome by homologous and illegitimate recombination. Mol Cell Biol 17: 267-77.
Sarkisian CJ, Keister BA, Stairs DB, Boxer RB, Moody SE, Chodosh LA (2007). Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat Cell Biol 9: 493-505.
Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM et al (2002). A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109: 335-46.
Schultz DC, Vanderveer L, Buetow KH, Boente MP, Ozols RF, Hamilton TC et al (1995). Characterization of chromosome 9 in human ovarian neoplasia identifies frequent genetic imbalance on 9q and rare alterations involving 9p, including CDKN2. Cancer Res 55: 2150-7.
Sedelnikova OA, Bonner WM (2006). GammaH2AX in cancer cells: a potential biomarker for cancer diagnostics, prediction and recurrence. Cell Cycle 5: 2909-13.
Sedelnikova OA, Pilch DR, Redon C, Bonner WM (2003). Histone H2AX in DNA damage and repair. Cancer Biol Ther 2: 233-5.
Seo HJ, Park HJ, Choi HS, Hwang SY, Park JS, Seong YS (2008). BMI-1026 treatment can induce SAHF formation by activation of Erk1/2. BMB Rep 41: 523-8.
Sharma RA, Dianov GL (2007). Targeting base excision repair to improve cancer therapies. Mol Aspects Med 28: 345-74.
Shay JW, Wright WE (2001). Aging. When do telomeres matter? Science 291: 839-40.
Shiloh Y (2006). The ATM-mediated DNA-damage response: taking shape. Trends in Biochemical Sciences 31: 402-410.
Shimada M, Niida H, Zineldeen DH, Tagami H, Tanaka M, Saito H et al (2008). Chk1 is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression. Cell 132: 221-32.
Shrivastav M, De Haro LP, Nickoloff JA (2008). Regulation of DNA double-strand break repair pathway choice. Cell Res 18: 134-47.
Srivastava N, Gochhait S, Gupta P, Bamezai RN (2008). Copy number alterations of the H2AFX gene in sporadic breast cancer patients. Cancer Genet Cytogenet 180: 121-8.
Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP (2005). MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123: 1213-26.
Sugasawa K, Okamoto T, Shimizu Y, Masutani C, Iwai S, Hanaoka F (2001). A multistep damage recognition mechanism for global genomic nucleotide excision repair. Genes Dev 15: 507-21.
Surpili MJ, Delben TM, Kobarg J (2003). Identification of proteins that interact with the central coiled-coil region of the human protein kinase NEK1. Biochemistry 42: 15369-76.
Suzuki T, Fujii M, Ayusawa D (2002). Demethylation of classical satellite 2 and 3 DNA with chromosomal instability in senescent human fibroblasts. Exp Gerontol 37: 1005-14.
Takahashi A, Ohnishi T (2005). Does gammaH2AX foci formation depend on the presence of DNA double strand breaks? Cancer Lett 229: 171-9.
Takai H, Smogorzewska A, de Lange T (2003). DNA damage foci at dysfunctional telomeres. Curr Biol 13: 1549-56.
Thirman MJ, Gill HJ, Burnett RC, Mbangkollo D, McCabe NR, Kobayashi H et al (1993). Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations. N Engl J Med 329: 909-14.
Turenne GA, Paul P, Laflair L, Price BD (2001). Activation of p53 transcriptional activity requires ATM's kinase domain and multiple N-terminal serine residues of p53. Oncogene 20: 5100-10.
van Gent DC, Hoeijmakers JH, Kanaar R (2001). Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2: 196-206.
Vojta PJ, Barrett JC (1995). Genetic analysis of cellular senescence. Biochim Biophys Acta 1242: 29-41.
Volker M, Mone MJ, Karmakar P, van Hoffen A, Schul W, Vermeulen W et al (2001). Sequential assembly of the nucleotide excision repair factors in vivo. Mol Cell 8: 213-24.
Wakasugi M, Kawashima A, Morioka H, Linn S, Sancar A, Mori T et al (2002). DDB accumulates at DNA damage sites immediately after UV irradiation and directly stimulates nucleotide excision repair. J Biol Chem 277: 1637-40.
Walen KH (2007). Origin of diplochromosomal polyploidy in near-senescent fibroblast cultures: heterochromatin, telomeres and chromosomal instability (CIN). Cell Biol Int 31: 1447-55.
Watson JD (1972). Origin of concatemeric T7 DNA. Nat New Biol 239: 197-201.
Wiesner C, Winsauer G, Resch U, Hoeth M, Schmid JA, van Hengel J et al (2008). Alpha-catulin, a Rho signalling component, can regulate NF-kappaB through binding to IKK-beta, and confers resistance to apoptosis. Oncogene 27: 2159-69.
Wilson DM, 3rd, Bohr VA (2007). The mechanics of base excision repair, and its relationship to aging and disease. DNA Repair (Amst) 6: 544-59.
Wu C, Miloslavskaya I, Demontis S, Maestro R, Galaktionov K (2004). Regulation of cellular response to oncogenic and oxidative stress by Seladin-1. Nature 432: 640-5.
Xiang Y, Tan YR, Zhang JS, Qin XQ, Hu BB, Wang Y et al (2008). Wound repair and proliferation of bronchial epithelial cells regulated by CTNNAL1. J Cell Biochem 103: 920-30.
Yang H, Wen YY, Zhao R, Lin YL, Fournier K, Yang HY et al (2006). DNA damage-induced protein 14-3-3 sigma inhibits protein kinase B/Akt activation and suppresses Akt-activated cancer. Cancer Res 66: 3096-105.
Zhang H (2007). Molecular signaling and genetic pathways of senescence: Its role in tumorigenesis and aging. J Cell Physiol 210: 567-74.
Zhang JS, Nelson M, Wang L, Liu W, Qian CP, Shridhar V et al (1998). Identification and chromosomal localization of CTNNAL1, a novel protein homologous to alpha-catenin. Genomics 54: 149-54.
Ziv Y, Bielopolski D, Galanty Y, Lukas C, Taya Y, Schultz DC et al (2006). Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nat Cell Biol 8: 870-6.
Zou L (2007). Single- and double-stranded DNA: building a trigger of ATR-mediated DNA damage response. Genes Dev 21: 879-85.
Zou X, Ray D, Aziyu A, Christov K, Boiko AD, Gudkov AV et al (2002). Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence. Genes Dev 16: 2923-34.
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