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系統識別號 U0026-2901201911411200
論文名稱(中文) 探討烷基類藥物引發之O6-甲基化鳥嘌呤-去氧核醣核酸甲基轉移酶泛素化的作用機轉及其臨床意義
論文名稱(英文) Investigation of the Mechanism Underlying the Ubiquitination of O6-Methylguanine-DNA Methyltransferase Induced by Alkylating Agents and Its Clinical Significance
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 107
學期 1
出版年 108
研究生(中文) 徐詩涵
研究生(英文) Shih-Han Hsu
學號 S58014017
學位類別 博士
語文別 英文
論文頁數 141頁
口試委員 指導教授-張俊彥
召集委員-洪文俊
口試委員-莊偉哲
口試委員-洪建中
口試委員-林鼎晏
口試委員-林常申
中文關鍵字 去氧核醣核酸甲基轉移酶甲基轉移酶  泛素結合酶  泛素化  格立得  順鉑 
英文關鍵字 MGMT  UBE2B  ubiquitination  BCNU  CDDP 
學科別分類
中文摘要 O6-甲基化鳥嘌呤-去氧核醣核酸甲基轉移酶 (MGMT) 為 DNA 修復酶,負責調控化療藥物在鳥嘌呤 O6 位置進行烷基化所導致的細胞毒性。然而,在先前多種癌細胞的研究中,發現格立得 (carmustine, BCNU) 及順鉑 (cisplatin, CDDP) 等烷基類藥物會透過不明機制促使 MGMT 分解。於本研究中,我們首次闡明了 E2 泛素結合酶 UBE2B 是個新穎的 MGMT 調控者,負責控制 BCNU 及 CDDP 造成之 MGMT 泛素化。而 UBE2B 的已知共同調控者,即 E3 泛素連結酶 RAD18,亦參與調控此 MGMT 泛素化過程。過量/抑制表現 UBE2B 會增加/減少 BCNU 導致之 MGMT 分解。令人感到驚奇的是,抑制 UBE2B 表現會顯著增強 BCNU 與 CDDP 的細胞毒殺效果,暗示若失去 UBE2B 會阻礙已被烷基修飾之 MGMT 與泛素結合並被分解的過程。我們發現抑制 UBE2B 表現後給予烷基類藥物,細胞中 MGMT 活性會降低,意味著失去 UBE2B 導致非活化態的 MGMT 大量累積,並阻擋 MGMT 蛋白質新陳代謝,最終導致細胞凋亡。臨床分析結果顯示,鼻咽癌病人患部組織有較高量 UBE2B 表現,且越高量 UBE2B 表現的病人預後越差。分析多種其他癌症亦得相似結果,表示此調控路徑可能存在於不同癌症環境中。本研究結果顯示 UBE2B 會透過調控 MGMT 而影響癌細胞對 BCNU 及 CDDP 的敏感度,且 UBE2B 可能是潛在的癌症預後參考指標。
英文摘要 The DNA repair enzyme, O6-methylguanine-DNA methyltransferase (MGMT), modulates the cytotoxicity of chemotherapeutic agents related to DNA alkylation of the O6-position of guanine. However, previous studies indicated that alkylating agents such as 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine, BCNU) and cisplatin (CDDP) facilitate MGMT degradation in several types of cancer cells with unclear mechanism. In this study, we demonstrate for the first time that ubiquitin-conjugating enzyme E2 B (UBE2B) is a novel regulator of MGMT ubiquitination mediated by BCNU and CDDP in various cancer cell lines. The E3 ubiquitin ligase RAD18, a partner of UBE2B, is also involved in MGMT ubiquitination. Overexpression/knockdown of UBE2B enhances/reduces BCNU-mediated MGMT degradation. Surprisingly, UBE2B knockdown significantly increases the cytotoxicity of BCNU and CDDP, indicating that loss of UBE2B disrupts ubiquitin-mediated degradation of alkylated MGMT. We found that UBE2B depletion reduces MGMT activity in BCNU-treated cells, suggesting that loss of UBE2B leads to the accumulation of deactivated MGMT, inhibition of MGMT protein turnover, and apoptosis in the end. Clinical analysis of patients with nasopharyngeal carcinoma (NPC) showed enhanced UBE2B expression in NPC tissues compared with normal nasopharynx. Various types of cancer patients with UBE2B overexpression showed poor survival. These findings indicate that UBE2B modulates the sensitivity to BCNU and CDDP in cancer cells by regulating MGMT ubiquitination, and UBE2B may be a potential marker of poor prognosis.
論文目次 Contents
中文摘要 II
Abstract III
Acknowledgment IV
Abbreviation V
Contents VI
Table Contents XI
Figure Contents XII
Introduction 1
1.1. The obstacle in cancer chemotherapy 2
1.2. Carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU) 3
1.3. Cisplatin (CDDP) 3
1.4. Function of O6-methylguanine-DNA methyltransferase (MGMT) 4
1.5. Role of MGMT in cancer therapy 4
1.6. MGMT expression is critical in nasopharyngeal carcinoma (NPC) and colorectal adenocarcinoma (CRC) cells 5
1.7. Ubiquitination 5
1.8. Protein degradation processes 6
1.9. Role of ubiquitin-proteasome system in cancer progression and therapy 7
1.10. Functions of ubiquitin-conjugating enzyme E2 B (UBE2B) and its related E3 ligases 7
1.11. The potential regulation of MGMT by UBE2B 8
1.12. Prediction of the binding affinity between MGMT and various ubiquitin-conjugating E2 enzymes 9
1.13. Hypothesis and specific aims 9
Materials and Methods 11
2.1. General approaches of each aim in this study 12
2.2. Cell culture 14
2.3. Antibodies and reagents 15
2.4. Western blotting 16
2.5. Prediction of the binding affinity between MGMT and ubiquitin-conjugating E2 enzymes 16
2.6. Immunofluorescence assay 17
2.7. Immunoprecipitation assay 18
2.8. Fluorometric MGMT activity assay 18
2.9. siRNA transfection and transient knockdown 19
2.10. Production of lentivirus particles and selection of stable cell lines 20
2.11. Plasmid construction 20
2.12. Prediction of the ubiquitination sites in MGMT 22
2.13. In-vitro ubiquitination assay 22
2.14. Mass spectrometry analysis 23
2.15. Cell viability assay 23
2.16. Clonogenic assay 24
2.17. Analysis of Oncomine database 24
2.18. Patients and tumor specimens 24
2.19. Immunohistochemistry and assessment of UBE2B expression 25
2.20. Treatment and follow-up of the patients 26
2.21. Statistical analysis 26
Results 28
3.1. BCNU decreases MGMT expression levels in human nasopharyngeal carcinoma (NPC) cells 29
3.2. BCNU facilitates MGMT degradation through ubiquitin-dependent proteasomal pathway 29
3.3. UBE2B exhibited the strongest binding affinity with MGMT among the candidate E2 enzymes in our prediction 30
3.4. RAD18 was chosen for analyzing its involvement in the ubiquitination of MGMT 30
3.5. BCNU enhances the interaction between MGMT and UBE2B/RAD18 31
3.6. UBE2B and RAD18 facilitate MGMT ubiquitination in vitro 32
3.7. Construction of pEGFPc1-MGMT 33
3.8. Co-IP of EGFP-MGMT and RAD18 in 293T cells confirmed the interaction of MGMT and RAD18 33
3.9. Prediction of the ubiquitination sites in human MGMT 33
3.10. Construction of pEGFPc1 plasmids containing various fragments of human MGMT 34
3.11. UBE2B is critical for BCNU sensitivity and BCNU-mediated MGMT ubiquitination in NPC cells 34
3.12. Accumulation of deactivated MGMT proteins in NPC cells causes cell death 35
3.13. BCNU, CDDP, and accumulated dysfunctional MGMT in NPC cells cause the cleavage of PARP 36
3.14. Depletion of UBE2B suppresses MGMT turnover in BCNU-treated HONE-1 cells 37
3.15. Lysosomes are not majorly involved in regulating BCNU-mediated MGMT degradation 37
3.16. The same regulation of MGMT by UBE2B exists in HT-29 cells 38
3.17. The interaction among MGMT, UBE2B, and RAD18 was confirmed in 293T and OEC-M1 models 39
3.18. CDDP enhances the interaction among MGMT, UBE2B, and RAD18 in NPC cells 39
3.19. Modulation of UBE2B expression affects the CDDP sensitivities in HONE-1, TW01, and HT-29 cells 40
3.20. NPC patients with higher UBE2B expressions showed worse prognosis 40
3.21. Cancer patients in other cohorts with enhanced UBE2B expressions showed poorer prognosis 41
Discussion and Perspectives 43
4.1. The post-translational regulation of MGMT by BCNU leads to ubiquitin-dependent proteolysis of MGMT and apoptosis of NPC cells 44
4.2. UBE2B and RAD18 are both involved in BCNU-mediated ubiquitination of MGMT 45
4.3. Perspectives for analyzing the detailed mechanism underlying MGMT ubiquitination 47
4.4. Similar regulation of MGMT by UBE2B and RAD18 was found in NPC cells and CRC cells 48
4.5. The regulation of MGMT by CDDP in NPC cells and CRC cells 48
4.6. The clinical implication of UBE2B in various cancer types 49
4.7. Potential application of the inhibitors against UBE2B or RAD18 in cancer therapy 50
4.8. Conclusion 51
References 52
Tables 73
Figures 82
Appendix 140

Table Contents
Table 1. Prediction of interactions between MGMT and E2 ubiquitin-conjugating enzymes. 74
Table 2. Primer sets and probe pairs. 75
Table 3. Mass spectrometry analysis of in-vitro ubiquitination samples 76
Table 4. Prediction of potential ubiquitination sites in MGMT by using various webservers and databases. 77
Table 5. IC50 values of BCNU and CDDP in control, 2BKD, 2BKD+MGMT, and R18KD cells. 78
Table 6. Associations between UBE2B expression levels and important clinicopathologic variables. 79
Table 7. Univariate log-rank analyses. 80
Table 8. Multivariate survival analyses. 81

Figure Contents
Figure 1. Inhibition of UBE2B and MGMT by miR-455-5p in human oral cancer cell lines. 83
Figure 2. Overexpression of MGMT and UBE2B in CDDP-resistant NPC cell lines Cis6 and Cis15. 84
Figure 3. BCNU decreases MGMT expression levels in NPC cells and reduces MGMT activity in vitro. 85
Figure 4. BCNU facilitates MGMT degradation in NPC cells via the ubiquitin-dependent proteasomal pathway. 88
Figure 5. PyDockWEB-predicted binding models of MGMT with various E2 ubiquitin-conjugating enzymes. 90
Figure 6. Screening of E3 ligases candidates for analyzing MGMT ubiquitination. 91
Figure 7. BCNU increases the interaction among MGMT, ubiquitinated UBE2B, and RAD18. 92
Figure 8. UBE2B and RAD18 accelerate the ubiquitination of MGMT in vitro. 95
Figure 9. Construction of pEGFPc1-MGMT. 96
Figure 10. Analysis of the interaction between MGMT and RAD18 by using 293T cell line as a model system. 99
Figure 11. Prediction of the ubiquitination sites in human MGMT. 100
Figure 12. Construction of pEGFPc1 plasmids containing various fragments of human MGMT. 106
Figure 13. Modulation of the UBE2B expression level regulates BCNU sensitivity and BCNU-induced MGMT ubiquitination in NPC cells. 114
Figure 14. Construction of plasmid pEGFPc1-MGMT-C145S. 118
Figure 15. Accumulated dysfunctional MGMT proteins facilitate cell death in NPC cells. 120
Figure 16. BCNU, CDDP, and the accumulation of dysfunctional MGMT protein induce the cleavage of PARP in NPC cells. 122
Figure 17. Depletion of UBE2B suppresses MGMT turnover in BCNU-treated cells. 124
Figure 18. The lysosome inhibitor chloroquine is not able to rescue BCNU-mediated MGMT degradation. 126
Figure 19. The regulation of MGMT by UBE2B in human colorectal adenocarcinoma cell line HT-29. 127
Figure 20. BCNU increases the ubiquitination of EGFP-MGMT and interaction of EGFP-MGMT and RAD18. 130
Figure 21. CDDP promotes the interactions among MGMT, UBE2B and RAD18 in NPC cells. 132
Figure 22. Modulation of the UBE2B expression level regulates CDDP sensitivities in HONE-1, TW01, and HT-29 cells. 133
Figure 23. NPC patients with increased UBE2B expressions showed worse prognosis. 134
Figure 24. Higher UBE2B expression is associated with poorer prognosis of various types of cancer patients. 136
Figure 25. Proposed model for the regulation of MGMT by UBE2B in cancer cells. 139


參考文獻 Babson, J. R. and D. J. Reed. "Inactivation of glutathione reductase by 2-chloroethyl nitrosourea-derived isocyanates." Biochem Biophys Res Commun 83: 754-762. (1978)

Bailly, V., J. Lamb, P. Sung, S. Prakash and L. Prakash. "Specific complex formation between yeast RAD6 and RAD18 proteins: a potential mechanism for targeting RAD6 ubiquitin-conjugating activity to DNA damage sites." Genes Dev 8: 811-820. (1994)

Bergink, S. and S. Jentsch. "Principles of ubiquitin and SUMO modifications in DNA repair." Nature 458: 461-467. (2009)

Bowdown, B. J. and G. P. Wheeler. "Reaction of 1,3-Bis(2-Chloroethyl)-1-Nitrosourea (Bcnu) with Protein." Proceedings of the American Association for Cancer Research 12: 67. (1971)

Cai, F., P. Chen, L. Chen, E. Biskup, Y. Liu, P. C. Chen, J. F. Chang, W. Jiang, Y. Jing, Y. Chen, H. Jin and S. Chen. "Human RAD6 promotes G1-S transition and cell proliferation through upregulation of cyclin D1 expression." PLoS One 9: e113727. (2014)

Chen, S. H., C. C. Kuo, C. F. Li, C. H. Cheung, T. C. Tsou, H. C. Chiang, Y. N. Yang, S. L. Chang, L. C. Lin, H. Y. Pan, K. Y. Chang and J. Y. Chang. "O(6) -methylguanine DNA methyltransferase repairs platinum-DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma." Int J Cancer 137: 1291-1305. (2015)

Chen, X., M. Liang and D. Wang. "Progress on the study of the mechanism of busulfan cytotoxicity." Cytotechnology 70: 497-502. (2018)

Chen, X., J. D. Qiu, S. P. Shi, S. B. Suo, S. Y. Huang and R. P. Liang. "Incorporating key position and amino acid residue features to identify general and species-specific Ubiquitin conjugation sites." Bioinformatics 29: 1614-1622. (2013)

Chen, Z., Y. Z. Chen, X. F. Wang, C. Wang, R. X. Yan and Z. Zhang. "Prediction of ubiquitination sites by using the composition of k-spaced amino acid pairs." PLoS One 6: e22930. (2011)

Chen, Z., Y. Zhou, J. Song and Z. Zhang. "hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties." Biochim Biophys Acta 1834: 1461-1467. (2013)

Cheng, C. M., S. G. Shiah, C. C. Huang, J. R. Hsiao and J. Y. Chang. "Up-regulation of miR-455-5p by the TGF-beta-SMAD signalling axis promotes the proliferation of oral squamous cancer cells by targeting UBE2B." J Pathol 240: 38-49. (2016)

Ciechanover, A. "Proteolysis: from the lysosome to ubiquitin and the proteasome." Nat Rev Mol Cell Biol 6: 79-87. (2005)

Crul, M., R. C. van Waardenburg, J. H. Beijnen and J. H. Schellens. "DNA-based drug interactions of cisplatin." Cancer Treat Rev 28: 291-303. (2002)

D'Atri, S., G. Graziani, P. M. Lacal, V. Nistico, S. Gilberti, I. Faraoni, A. J. Watson, E. Bonmassar and G. P. Margison. "Attenuation of O(6)-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in jurkat cells." J Pharmacol Exp Ther 294: 664-671. (2000)

Daniels, D. S., T. T. Woo, K. X. Luu, D. M. Noll, N. D. Clarke, A. E. Pegg and J. A. Tainer. "DNA binding and nucleotide flipping by the human DNA repair protein AGT." Nat Struct Mol Biol 11: 714-720. (2004)

David, J. C., T. Bassez, M. Bonhommet and R. Rusquet. "Inhibition of DNA ligase from human thymocytes and normal or leukemic lymphocytes by antileukemic drugs." Cancer Res 45: 2177-2183. (1985)

Edge, S. B. and C. C. Compton. "The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM." Ann Surg Oncol 17: 1471-1474. (2010)

Ferreira, J., A. A. Ramos, T. Almeida, A. Azqueta and E. Rocha. "Drug resistance in glioblastoma and cytotoxicity of seaweed compounds, alone and in combination with anticancer drugs: A mini review." Phytomedicine 48: 84-93. (2018)

Ferreri, A. J. M. "Therapy of primary CNS lymphoma: role of intensity, radiation, and novel agents." Hematology Am Soc Hematol Educ Program 2017: 565-577. (2017)

Fischhaber, P. L., A. S. Gall, J. A. Duncan and P. B. Hopkins. "Direct demonstration in synthetic oligonucleotides that N,N'-bis(2-chloroethyl)-nitrosourea cross links N1 of deoxyguanosine to N3 of deoxycytidine on opposite strands of duplex DNA." Cancer Res 59: 4363-4368. (1999)

Fornace, A. J., Jr., K. W. Kohn and H. E. Kann, Jr. "Inhibition of the ligase step of excision repair by 2-chloroethyl isocyanate, a decomposition product of 1,3-bis(2-chloroethyl)-1-nitrosourea." Cancer Res 38: 1064-1069. (1978)

Fraile, J. M., V. Quesada, D. Rodriguez, J. M. Freije and C. Lopez-Otin. "Deubiquitinases in cancer: new functions and therapeutic options." Oncogene 31: 2373-2388. (2012)

Gaedcke, J., M. Grade, K. Jung, J. Camps, P. Jo, G. Emons, A. Gehoff, U. Sax, M. Schirmer, H. Becker, T. Beissbarth, T. Ried and B. M. Ghadimi. "Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas." Genes Chromosomes Cancer 49: 1024-1034. (2010)

Gallo, L. H., J. Ko and D. J. Donoghue. "The importance of regulatory ubiquitination in cancer and metastasis." Cell Cycle 16: 634-648. (2017)

Game, J. C. and S. B. Chernikova. "The role of RAD6 in recombinational repair, checkpoints and meiosis via histone modification." DNA Repair (Amst) 8: 470-482. (2009)

Ge, Z., J. S. Leighton, Y. Wang, X. Peng, Z. Chen, H. Chen, Y. Sun, F. Yao, J. Li, H. Zhang, J. Liu, C. D. Shriver, H. Hu, N. Cancer Genome Atlas Research, H. Piwnica-Worms, L. Ma and H. Liang. "Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types." Cell Rep 23: 213-226 e213. (2018)

Gerson, S. L. "Clinical relevance of MGMT in the treatment of cancer." J Clin Oncol 20: 2388-2399. (2002)

Gerson, S. L. "MGMT: its role in cancer aetiology and cancer therapeutics." Nat Rev Cancer 4: 296-307. (2004)

Glaser, R., H. Y. Zhang, K. T. Yao, H. C. Zhu, F. X. Wang, G. Y. Li, D. S. Wen and Y. P. Li. "Two epithelial tumor cell lines (HNE-1 and HONE-1) latently infected with Epstein-Barr virus that were derived from nasopharyngeal carcinomas." Proc Natl Acad Sci U S A 86: 9524-9528. (1989)

Guo, Y., Y. Song, Z. Guo, M. Hu, B. Liu, H. Duan, L. Wang, T. Yuan and D. Wang. "Function of RAD6B and RNF8 in spermatogenesis." Cell Cycle 17: 162-173. (2018)

Hazra, T. K., R. Roy, T. Biswas, D. T. Grabowski, A. E. Pegg and S. Mitra. "Specific recognition of O6-methylguanine in DNA by active site mutants of human O6-methylguanine-DNA methyltransferase." Biochemistry 36: 5769-5776. (1997)

Hershko, A. and A. Ciechanover. "The ubiquitin system." Annu Rev Biochem 67: 425-479. (1998)

Hoege, C., B. Pfander, G. L. Moldovan, G. Pyrowolakis and S. Jentsch. "RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO." Nature 419: 135-141. (2002)

Hoeller, D. and I. Dikic. "Targeting the ubiquitin system in cancer therapy." Nature 458: 438-444. (2009)

Hongo, A., R. Gu, M. Suzuki, N. Nemoto and K. Nishigaki. "A radioisotope-nondependent high-sensitivity method for measuring the activity of glioblastoma-related O(6)-methylguanine DNA methyltransferase." Anal Biochem 480: 82-84. (2015)

Hornbeck, P. V., J. M. Kornhauser, S. Tkachev, B. Zhang, E. Skrzypek, B. Murray, V. Latham and M. Sullivan. "PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse." Nucleic Acids Res 40: D261-270. (2012)

Hwang, C. S., A. Shemorry and A. Varshavsky. "Two proteolytic pathways regulate DNA repair by cotargeting the Mgt1 alkylguanine transferase." Proc Natl Acad Sci U S A 106: 2142-2147. (2009)

Jimenez-Garcia, B., C. Pons and J. Fernandez-Recio. "pyDockWEB: a web server for rigid-body protein-protein docking using electrostatics and desolvation scoring." Bioinformatics 29: 1698-1699. (2013)

Jones, J. S., S. Weber and L. Prakash. "The Saccharomyces cerevisiae RAD18 gene encodes a protein that contains potential zinc finger domains for nucleic acid binding and a putative nucleotide binding sequence." Nucleic Acids Res 16: 7119-7131. (1988)

Joo, J. H., J. K. Rho, J. H. Kim, W. J. Kim, S. Y. Choe and S. D. Park. "Expression of yeast O6-methylguanine-DNA methyltransferase (MGMT) gene." Cell Mol Biol (Noisy-le-grand) 41: 545-553. (1995)

Kanao, R. and C. Masutani. "Regulation of DNA damage tolerance in mammalian cells by post-translational modifications of PCNA." Mutat Res 803-805: 82-88. (2017)

Kannouche, P. L., J. Wing and A. R. Lehmann. "Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage." Mol Cell 14: 491-500. (2004)

Kee, Y. and T. T. Huang. "Role of Deubiquitinating Enzymes in DNA Repair." Mol Cell Biol 36: 524-544. (2016)

Kreklau, E. L., M. Limp-Foster, N. Liu, Y. Xu, M. R. Kelley and L. C. Erickson. "A novel fluorometric oligonucleotide assay to measure O( 6)-methylguanine DNA methyltransferase, methylpurine DNA glycosylase, 8-oxoguanine DNA glycosylase and abasic endonuclease activities: DNA repair status in human breast carcinoma cells overexpressing methylpurine DNA glycosylase." Nucleic Acids Res 29: 2558-2566. (2001)

Kumar, B., K. G. Lecompte, J. M. Klein and A. L. Haas. "Ser(120) of Ubc2/Rad6 regulates ubiquitin-dependent N-end rule targeting by E3α/Ubr1." J Biol Chem 285: 41300-41309. (2010)

Kuo, C. C., H. P. Hsieh, W. Y. Pan, C. P. Chen, J. P. Liou, S. J. Lee, Y. L. Chang, L. T. Chen, C. T. Chen and J. Y. Chang. "BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo." Cancer Res 64: 4621-4628. (2004)

Kuo, C. C., J. F. Liu and J. Y. Chang. "DNA repair enzyme, O6-methylguanine DNA methyltransferase, modulates cytotoxicity of camptothecin-derived topoisomerase I inhibitors." J Pharmacol Exp Ther 316: 946-954. (2006)

Kuo, C. C., J. F. Liu, H. S. Shiah, L. C. Ma and J. Y. Chang. "Tamoxifen accelerates proteasomal degradation of O6-methylguanine DNA methyltransferase in human cancer cells." Int J Cancer 121: 2293-2300. (2007)

Kuo, C. C., T. W. Liu, L. T. Chen, H. S. Shiah, C. M. Wu, Y. T. Cheng, W. Y. Pan, J. F. Liu, K. L. Chen, Y. N. Yang, S. N. Chen and J. Y. Chang. "Combination of arsenic trioxide and BCNU synergistically triggers redox-mediated autophagic cell death in human solid tumors." Free Radic Biol Med 51: 2195-2209. (2011)

Lambert, I. H. and B. H. Sorensen. "Facilitating the Cellular Accumulation of Pt-Based Chemotherapeutic Drugs." Int J Mol Sci 19. (2018)

Lawrence, C. W. "Following the RAD6 pathway." DNA Repair (Amst) 6: 676-686. (2007)

Lee, Y. Y., T. B. Chao, M. J. Sheu, Y. F. Tian, T. J. Chen, S. W. Lee, H. L. He, I. W. Chang, C. H. Hsing, C. Y. Lin and C. F. Li. "Glutamate Decarboxylase 1 Overexpression as a Poor Prognostic Factor in Patients with Nasopharyngeal Carcinoma." J Cancer 7: 1716-1723. (2016)

Lin, C. T., C. I. Wong, W. Y. Chan, K. W. Tzung, J. K. Ho, M. M. Hsu and S. M. Chuang. "Establishment and characterization of two nasopharyngeal carcinoma cell lines." Lab Invest 62: 713-724. (1990)

Lin, J. C., J. S. Jan, C. Y. Hsu, W. M. Liang, R. S. Jiang and W. Y. Wang. "Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival." J Clin Oncol 21: 631-637. (2003)

Liu, J., S. Shaik, X. Dai, Q. Wu, X. Zhou, Z. Wang and W. Wei. "Targeting the ubiquitin pathway for cancer treatment." Biochim Biophys Acta 1855: 50-60. (2015)

Liu, L., C. C. Wong, B. Gong and J. Yu. "Functional significance and therapeutic implication of ring-type E3 ligases in colorectal cancer." Oncogene 37: 148-159. (2018)

Lou, P., X. Sun, J. Zhou and S. Zou. "[Effect of RAD18-siRNA on proliferation and chemotherapy sensitivity of human esophageal squamous cell carcinoma ECA-109 cells]." Zhejiang Da Xue Xue Bao Yi Xue Ban 45: 364-370. (2016)

Lyakhovich, A. and M. P. Shekhar. "RAD6B overexpression confers chemoresistance: RAD6 expression during cell cycle and its redistribution to chromatin during DNA damage-induced response." Oncogene 23: 3097-3106. (2004)

Ma, L. C., C. C. Kuo, J. F. Liu, L. T. Chen and J. Y. Chang. "Transcriptional repression of O6-methylguanine DNA methyltransferase gene rendering cells hypersensitive to N,N'-bis(2-chloroethyl)-N-nitrosurea in camptothecin-resistant cells." Mol Pharmacol 74: 517-526. (2008)

Malhotra, V. and M. C. Perry. "Classical chemotherapy: mechanisms, toxicities and the therapeutic window." Cancer Biol Ther 2: S2-4. (2003)

Mani, A. and E. P. Gelmann. "The ubiquitin-proteasome pathway and its role in cancer." J Clin Oncol 23: 4776-4789. (2005)
Mansour, M. A. "Ubiquitination: Friend and foe in cancer." Int J Biochem Cell Biol 101: 80-93. (2018)

Mashiach, E., R. Nussinov and H. J. Wolfson. "FiberDock: a web server for flexible induced-fit backbone refinement in molecular docking." Nucleic Acids Res 38: W457-461. (2010)

Mashiach, E., R. Nussinov and H. J. Wolfson. "FiberDock: Flexible induced-fit backbone refinement in molecular docking." Proteins 78: 1503-1519. (2010)

Masuda, Y., M. Suzuki, H. Kawai, A. Hishiki, H. Hashimoto, C. Masutani, T. Hishida, F. Suzuki and K. Kamiya. "En bloc transfer of polyubiquitin chains to PCNA in vitro is mediated by two different human E2-E3 pairs." Nucleic Acids Res 40: 10394-10407. (2012)

McManus, F. P., Q. Fang, J. D. Booth, A. M. Noronha, A. E. Pegg and C. J. Wilds. "Synthesis and characterization of an O(6)-2'-deoxyguanosine-alkyl-O(6)-2'-deoxyguanosine interstrand cross-link in a 5'-GNC motif and repair by human O(6)-alkylguanine-DNA alkyltransferase." Org Biomol Chem 8: 4414-4426. (2010)

Metzger, M. B., J. N. Pruneda, R. E. Klevit and A. M. Weissman. "RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination." Biochim Biophys Acta 1843: 47-60. (2014)

Mostofa, A., S. R. Punganuru, H. R. Madala and K. S. Srivenugopal. "S-phase Specific Downregulation of Human O(6)-Methylguanine DNA Methyltransferase (MGMT) and its Serendipitous Interactions with PCNA and p21(cip1) Proteins in Glioma Cells." Neoplasia 20: 305-323. (2018)

Newton, K. and D. Vucic. "Ubiquitin ligases in cancer: ushers for degradation." Cancer Invest 25: 502-513. (2007)

Nguyen, V. N., K. Y. Huang, J. T. Weng, K. R. Lai and T. Y. Lee. "UbiNet: an online resource for exploring the functional associations and regulatory networks of protein ubiquitylation." Database (Oxford) 2016: 1-14. (2016)

Nikolova, T., W. P. Roos, O. H. Kramer, H. M. Strik and B. Kaina. "Chloroethylating nitrosoureas in cancer therapy: DNA damage, repair and cell death signaling." Biochim Biophys Acta Rev Cancer 1868: 29-39. (2017)

Nistico, R., F. Florenzano, D. Mango, C. Ferraina, M. Grilli, S. Di Prisco, A. Nobili, S. Saccucci, M. D'Amelio, M. Morbin, M. Marchi, N. B. Mercuri, R. J. Davis, A. Pittaluga and M. Feligioni. "Presynaptic c-Jun N-terminal Kinase 2 regulates NMDA receptor-dependent glutamate release." Sci Rep 5: 9035. (2015)

Ohta, T. and M. Fukuda. "Ubiquitin and breast cancer." Oncogene 23: 2079-2088. (2004)

Pegg, A. E. "Repair of O(6)-alkylguanine by alkyltransferases." Mutat Res 462: 83-100. (2000)

Pegg, A. E. "Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools." Chem Res Toxicol 24: 618-639. (2011)

Pfoh, R., I. K. Lacdao and V. Saridakis. "Deubiquitinases and the new therapeutic opportunities offered to cancer." Endocr Relat Cancer 22: T35-54. (2015)

Radivojac, P., V. Vacic, C. Haynes, R. R. Cocklin, A. Mohan, J. W. Heyen, M. G. Goebl and L. M. Iakoucheva. "Identification, analysis, and prediction of protein ubiquitination sites." Proteins 78: 365-380. (2010)

Raguz, S., C. Adams, N. Masrour, S. Rasul, P. Papoutsoglou, Y. Hu, G. Cazzanelli, Y. Zhou, N. Patel, C. Coombes and E. Yague. "Loss of O(6)-methylguanine-DNA methyltransferase confers collateral sensitivity to carmustine in topoisomerase II-mediated doxorubicin resistant triple negative breast cancer cells." Biochem Pharmacol 85: 186-196. (2013)

Ravid, T. and M. Hochstrasser. "Diversity of degradation signals in the ubiquitin-proteasome system." Nat Rev Mol Cell Biol 9: 679-690. (2008)

Rhodes, D. R., J. Yu, K. Shanker, N. Deshpande, R. Varambally, D. Ghosh, T. Barrette, A. Pandey and A. M. Chinnaiyan. "ONCOMINE: a cancer microarray database and integrated data-mining platform." Neoplasia 6: 1-6. (2004)

Rice, K. P., P. G. Penketh, K. Shyam and A. C. Sartorelli. "Differential inhibition of cellular glutathione reductase activity by isocyanates generated from the antitumor prodrugs Cloretazine and BCNU." Biochem Pharmacol 69: 1463-1472. (2005)

Rosenberg, B., L. VanCamp, J. E. Trosko and V. H. Mansour. "Platinum compounds: a new class of potent antitumour agents." Nature 222: 385-386. (1969)

Sanders, M. A., G. Brahemi, P. Nangia-Makker, V. Balan, M. Morelli, H. Kothayer, A. D. Westwell and M. P. V. Shekhar. "Novel inhibitors of Rad6 ubiquitin conjugating enzyme: design, synthesis, identification, and functional characterization." Mol Cancer Ther 12: 373-383. (2013)

Sanders, M. A., B. Haynes, P. Nangia-Makker, L. A. Polin and M. P. Shekhar. "Pharmacological targeting of RAD6 enzyme-mediated translesion synthesis overcomes resistance to platinum-based drugs." J Biol Chem 292: 10347-10363. (2017)

Sassanfar, M. and L. Samson. "Identification and preliminary characterization of an O6-methylguanine DNA repair methyltransferase in the yeast Saccharomyces cerevisiae." J Biol Chem 265: 20-25. (1990)

Schabel, F. M., Jr., T. P. Johnston, C. G. Mc, J. A. Montgomery, W. R. Laster and H. E. Skipper. "Experimental evaluation of potential anticancer agents VIII. Effects of certain nitrosoureas on intracerebral L1210 leukemia." Cancer Res 23: 725-733. (1963)

Schmall, B., C. J. Cheng, S. Fujimura, N. Gersten, D. Grunberger and I. B. Weinstein. "Modification of proteins by 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (nsc 79037) in vitro." Cancer Res 33: 1921-1924. (1973)

Schneidman-Duhovny, D., Y. Inbar, R. Nussinov and H. J. Wolfson. "PatchDock and SymmDock: servers for rigid and symmetric docking." Nucleic Acids Res 33: W363-367. (2005)

Sengupta, S., J. A. den Boon, I. H. Chen, M. A. Newton, D. B. Dahl, M. Chen, Y. J. Cheng, W. H. Westra, C. J. Chen, A. Hildesheim, B. Sugden and P. Ahlquist. "Genome-wide expression profiling reveals EBV-associated inhibition of MHC class I expression in nasopharyngeal carcinoma." Cancer Res 66: 7999-8006. (2006)

Singh, R. K., S. Kumar, D. N. Prasad and T. R. Bhardwaj. "Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives." Eur J Med Chem 151: 401-433. (2018)

Skinner, W. A., H. F. Gram, M. O. Greene, J. Greenberg and B. R. Baker. "Potential anticancer agents. XXXI. The relationship of chemical structure to antileukaemic activity with analogues of 1-methyl-3-nitro-1-nitrosoguanidine (NSC-9369)." J Med Pharm Chem 2: 299-333. (1960)

Srivenugopal, K. S., X. H. Yuan, H. S. Friedman and F. Ali-Osman. "Ubiquitination-dependent proteolysis of O6-methylguanine-DNA methyltransferase in human and murine tumor cells following inactivation with O6-benzylguanine or 1,3-bis(2-chloroethyl)-1-nitrosourea." Biochemistry 35: 1328-1334. (1996)

Stewart, M. D., T. Ritterhoff, R. E. Klevit and P. S. Brzovic. "E2 enzymes: more than just middle men." Cell Res 26: 423-440. (2016)

Sun, Y. "Targeting E3 ubiquitin ligases for cancer therapy." Cancer Biol Ther 2: 623-629. (2003)

Sun, Y. "E3 ubiquitin ligases as cancer targets and biomarkers." Neoplasia 8: 645-654. (2006)

Tedesco, D., J. Zhang, L. Trinh, G. Lalehzadeh, R. Meisner, K. D. Yamaguchi, D. L. Ruderman, H. Dinter and D. A. Zajchowski. "The ubiquitin-conjugating enzyme E2-EPF is overexpressed in primary breast cancer and modulates sensitivity to topoisomerase II inhibition." Neoplasia 9: 601-613. (2007)

Thompson, L. "World Health Organization classification of tumours: pathology and genetics of head and neck tumours." Ear Nose Throat J 85: 74. (2006)

Tintore, M., A. Avino, F. M. Ruiz, R. Eritja and C. Fabrega. "Development of a Novel Fluorescence Assay Based on the Use of the Thrombin-Binding Aptamer for the Detection of O-Alkylguanine-DNA Alkyltransferase Activity." J Nucleic Acids 2010: 1-9. (2010)

Tsuji, Y., K. Watanabe, K. Araki, M. Shinohara, Y. Yamagata, T. Tsurimoto, F. Hanaoka, K. Yamamura, M. Yamaizumi and S. Tateishi. "Recognition of forked and single-stranded DNA structures by human RAD18 complexed with RAD6B protein triggers its recruitment to stalled replication forks." Genes Cells 13: 343-354. (2008)

Tung, C. W. and S. Y. Ho. "Computational identification of ubiquitylation sites from protein sequences." BMC Bioinformatics 9: 310. (2008)

Turrisi, A. T., 3rd. "Platinum combined with radiation therapy in small cell lung cancer: focusing like a laser beam on crucial issues." Semin Oncol 21: 36-42. (1994)

Ulrich, H. D. "The RAD6 pathway: control of DNA damage bypass and mutagenesis by ubiquitin and SUMO." Chembiochem 6: 1735-1743. (2005)

Viel, T., P. Monfared, S. Schelhaas, I. B. Fricke, M. T. Kuhlmann, C. Fraefel and A. H. Jacobs. "Optimizing glioblastoma temozolomide chemotherapy employing lentiviral-based anti-MGMT shRNA technology." Mol Ther 21: 570-579. (2013)

Wolden, S. L., M. J. Zelefsky, D. H. Kraus, K. E. Rosenzweig, L. M. Chong, A. R. Shaha, H. Zhang, L. B. Harrison, J. P. Shah and D. G. Pfister. "Accelerated concomitant boost radiotherapy and chemotherapy for advanced nasopharyngeal carcinoma." J Clin Oncol 19: 1105-1110. (2001)

Wood, A., J. Schneider, J. Dover, M. Johnston and A. Shilatifard. "The Bur1/Bur2 complex is required for histone H2B monoubiquitination by Rad6/Bre1 and histone methylation by COMPASS." Mol Cell 20: 589-599. (2005)

Wu, Z., J. Liu, Q. D. Zhang, D. K. Lv, N. F. Wu and J. Q. Zhou. "Rad6-Bre1-mediated H2B ubiquitination regulates telomere replication by promoting telomere-end resection." Nucleic Acids Res 45: 3308-3322. (2017)

Xiao, W. and L. Samson. "The Saccharomyces cerevisiae MGT1 DNA repair methyltransferase gene: its promoter and entire coding sequence, regulation and in vivo biological functions." Nucleic Acids Res 20: 3599-3606. (1992)

Xu-Welliver, M. and A. E. Pegg. "Degradation of the alkylated form of the DNA repair protein, O(6)-alkylguanine-DNA alkyltransferase." Carcinogenesis 23: 823-830. (2002)

Yin, J., J. M. Zhu and X. Z. Shen. "The role and therapeutic implications of RING-finger E3 ubiquitin ligases in hepatocellular carcinoma." Int J Cancer 136: 249-257. (2015)

Zacharioudakis, E., P. Agarwal, A. Bartoli, N. Abell, L. Kunalingam, V. Bergoglio, B. Xhemalce, K. M. Miller and R. Rodriguez. "Chromatin Regulates Genome Targeting with Cisplatin." Angew Chem Int Ed Engl 56: 6483-6487. (2017)

Zhang, W., Z. Qin, X. Zhang and W. Xiao. "Roles of sequential ubiquitination of PCNA in DNA-damage tolerance." FEBS Lett 585: 2786-2794. (2011)

Zhang, W. and S. S. Sidhu. "Development of inhibitors in the ubiquitination cascade." FEBS Lett 588: 356-367. (2014)

Zhang, X. J., S. Chen, K. X. Huang and W. D. Le. "Why should autophagic flux be assessed?" Acta Pharmacol Sin 34: 595-599. (2013)

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