Function of human nucleic acid alkylation damage repair enzyme ALKBH3 in cancer progression and oncotherapy

doi:10.3969/j.issn.1674-8115.2021.05.021

Abstract

Abstract:

Human nucleic acid alkylation damage repair enzyme ALKBH3 (alpha-ketoglutarate-dependent dioxygenase homolog 3) belongs to Fe²⁺/α-Ketoglutarate (α-KG)-dependent AlkB dioxygenase family, and shares a highly conserved catalytic domain through the entire family. ALKBH3 specifically recognizes N¹-methyl adenine and N³-methyl cytosine on single-stranded DNA or RNA, and catalyzes their methyl group removal for alkylation damage repair. Previous studies have shown that ALKBH3 is highly expressed in various solid tumors, and thereby it has been considered as a potential anti-tumor drug target. Research of the structural function and regulation mechanism of ALKBH3 will help further understand the molecular mechanism in the DNA alkylation damage repair, and lay the foundation for the development of anti-tumor drugs targeting ALKBH3.

Key words: alpha-ketoglutarate-dependent dioxygenase homolog 3, ALKBH3, DNA alkylation damage repair, cancer

CLC Number:

Jing-yan HU, Lin ZHANG, Liang ZHANG. Function of human nucleic acid alkylation damage repair enzyme ALKBH3 in cancer progression and oncotherapy[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(5): 684-689.

Figures/Tables 1

TrendMD

References 46

1	Sedgwick B. Repairing DNA-methylation damage[J]. Nat Rev Mol Cell Biol, 2004, 5(2): 148-157.
2	Taverna P, Sedgwick B. Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli[J]. J Bacteriol, 1996, 178(17): 5105-5111.
3	Samson L, Cairns J. A new pathway for DNA repair in Escherichia coli[J]. Nature, 1977, 267(5608): 281-283.
4	Trewick SC, Henshaw TF, Hausinger RP, et al. Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage[J]. Nature, 2002, 419(6903): 174-178.
5	Chen FY, Tang Q, Bian K, et al. Adaptive response enzyme AlkB preferentially repairs 1-methylguanine and 3-methylthymine adducts in double-stranded DNA[J]. Chem Res Toxicol, 2016, 29(4): 687-693.
6	Delaney JC, Smeester L, Wong C, et al. AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo[J]. Nat Struct Mol Biol, 2005, 12(10): 855-860.
7	Liu Y, Yuan Q, Xie L. The AlkB family of Fe (II)/alpha-ketoglutarate-dependent dioxygenases modulates embryogenesis through epigenetic regulation[J]. Curr Stem Cell Res Ther, 2018, 13(2): 136-143.
8	Yi C, Yang CG, He C. A non-heme iron-mediated chemical demethylation in DNA and RNA[J]. Acc Chem Res, 2009, 42(4): 519-529.
9	Hausinger RP. Fe(II)/alpha-ketoglutarate-dependent hydroxylases and related enzymes[J]. Crit Rev Biochem Mol Biol, 2004, 39(1): 21-68.
10	Liu FG, Clark W, Luo GZ, et al. ALKBH₁-mediated tRNA demethylation regulates translation[J]. Cell, 2016, 167(7): 1897.
11	Tian LF, Liu YP, Chen LQ, et al. Structural basis of nucleic acid recognition and 6mA demethylation by human ALKBH₁[J]. Cell Res, 2020, 30(3): 272-275.
12	Zhang M, Yang SM, Nelakanti R, et al. Mammalian ALKBH₁ serves as an N⁶-mA demethylase of unpairing DNA[J]. Cell Res, 2020, 30(3): 197-210.
13	Xu C, Liu K, Tempel W, et al. Structures of human ALKBH₅ demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation[J]. J Biol Chem, 2014, 289(25): 17299-17311.
14	Gerken T, Girard CA, Tung YC, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase[J]. Science, 2007, 318(5855): 1469-1472.
15	Zhang X, Wei LH, Wang YX, et al. Structural insights into FTO′s catalytic mechanism for the demethylation of multiple RNA substrates[J]. Proc Natl Acad Sci USA, 2019, 116(8): 2919-2924.
16	Chen BE, Liu HC, Sun XX, et al. Mechanistic insight into the recognition of single-stranded and double-stranded DNA substrates by ABH₂ and ABH₃[J]. Mol Biosyst, 2010, 6(11): 2143-2149.
17	Duncan T, Trewick SC, Koivisto P, et al. Reversal of DNA alkylation damage by two human dioxygenases[J]. Proc Natl Acad Sci USA, 2002, 99(26): 16660-16665.
18	Li MM, Nilsen A, Shi Y, et al. ALKBH₄-dependent demethylation of actin regulates actomyosin dynamics[J]. Nat Commun, 2013, 4: 1832.
19	Fu D, Jordan JJ, Samson LD. Human ALKBH₇ is required for alkylation and oxidation-induced programmed necrosis[J]. Genes Dev, 2013, 27(10): 1089-1100.
20	Jordan JJ, Chhim S, Margulies CM, et al. ALKBH₇ drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage[J]. Cell Death Dis, 2017, 8(7): e2947.
21	Ohshio I, Kawakami R, Tsukada Y, et al. ALKBH₈ promotes bladder cancer growth and progression through regulating the expression of survivin[J]. Biochem Biophys Res Commun, 2016, 477(3): 413-418.
22	Fedeles BI, Singh V, Delaney JC, et al. The AlkB family of Fe(II)/α-ketoglutarate-dependent dioxygenases: repairing nucleic acid alkylation damage and beyond[J]. J Biol Chem, 2015, 290(34): 20734-20742.
23	Lee DH, Jin SG, Cai S, et al. Repair of methylation damage in DNA and RNA by mammalian AlkB homologues[J]. J Biol Chem, 2005, 280(47): 39448-39459.
24	Aas PA, Otterlei M, Falnes PO, et al. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA[J]. Nature, 2003, 421(6925): 859-863.
25	Sundheim O, Vågbø CB, Bjørås M, et al. Human ABH₃ structure and key residues for oxidative demethylation to reverse DNA/RNA damage[J]. EMBO J, 2006, 25(14): 3389-3397.
26	Yang CG, Yi CQ, Duguid EM, et al. Crystal structures of DNA/RNA repair enzymes AlkB and ABH₂ bound to dsDNA[J]. Nature, 2008, 452(7190): 961-965.
27	Monsen VT, Sundheim O, Aas PA, et al. Divergent ß-hairpins determine double-strand versus single-strand substrate recognition of human AlkB-homologues 2 and 3[J]. Nucleic Acids Res, 2010, 38(19): 6447-6455.
28	Dango S, Mosammaparast N, Sowa ME, et al. DNA unwinding by ASCC₃ helicase is coupled to ALKBH₃-dependent DNA alkylation repair and cancer cell proliferation[J]. Mol Cell, 2011, 44(3): 373-384.
29	Brickner JR, Soll JM, Lombardi PM, et al. A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair[J]. Nature, 2017, 551(7680): 389-393.
30	Yoshizawa S, Fourmy D, Puglisi JD. Recognition of the Codon-anticodon helix by ribosomal RNA[J]. Science, 1999, 285(5434): 1722-1725.
31	Li XY, Xiong XS, Wang K, et al. Transcriptome-wide mapping reveals reversible and dynamic N¹-methyladenosine methylome[J]. Nat Chem Biol, 2016, 12(5): 311-316.
32	Ueda Y, Ooshio I, Fusamae Y, et al. AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells[J]. Sci Rep, 2017, 7: 42271.
33	Chen ZJ, Qi MJ, Shen B, et al. Transfer RNA demethylase ALKBH₃ promotes cancer progression via induction of tRNA-derived small RNAs[J]. Nucleic Acids Res, 2019, 47(5): 2533-2545.
34	Moore LD, Le T, Fan G. DNA methylation and its basic function[J]. Neuropsychopharmacology, 2013, 38(1): 23-38.
35	Liefke R, Windhof-Jaidhauser IM, Gaedcke J, et al. The oxidative demethylase ALKBH₃ marks hyperactive gene promoters in human cancer cells[J]. Genome Med, 2015, 7(1): 66.
36	Konishi N, Nakamura M, Ishida E, et al. High expression of a new marker PCA-1 in human prostate carcinoma[J]. Clin Cancer Res, 2005, 11(14): 5090-5097.
37	Koike K, Ueda Y, Hase H, et al. Anti-tumor effect of AlkB homolog 3 knockdown in hormone- independent prostate cancer cells[J]. Curr Cancer Drug Targets, 2012, 12(7): 847-856.
38	Pilžys T, Marcinkowski M, Kukwa W, et al. ALKBH overexpression in head and neck cancer: potential target for novel anticancer therapy[J]. Sci Rep, 2019, 9(1): 13249.
39	Yamato I, Sho M, Shimada K, et al. PCA-1/ALKBH₃ contributes to pancreatic cancer by supporting apoptotic resistance and angiogenesis[J]. Cancer Res, 2012, 72(18): 4829-4839.
40	Tasaki M, Shimada K, Kimura H, et al. ALKBH3, a human AlkB homologue, contributes to cell survival in human non-small-cell lung cancer[J]. Br J Cancer, 2011, 104(4): 700-706.
41	Woo HH, Chambers SK. Human ALKBH₃-induced m¹A demethylation increases the CSF-1 mRNA stability in breast and ovarian cancer cells[J]. Biochim Biophys Acta Gene Regul Mech, 2019, 1862(1): 35-46.
42	Hotta K, Sho M, Fujimoto K, et al. Clinical significance and therapeutic potential of prostate cancer antigen-1/ALKBH₃ in human renal cell carcinoma[J]. Oncol Rep, 2015, 34(2): 648-654.
43	Wang Q, Wang G, Wang Y, et al. Association of AlkB homolog 3 expression with tumor recurrence and unfavorable prognosis in hepatocellular carcinoma[J]. J Gastroenterol Hepatol, 2018, 33(9):1617-1625.
44	Nakao S, Mabuchi M, Shimizu T, et al. Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH₃) inhibitors as anti-prostate cancer drugs[J]. Bioorg Med Chem Lett, 2014, 24(4): 1071-1074.
45	Nigam R, Babu KR, Ghosh T, et al. Indenone derivatives as inhibitor of human DNA dealkylation repair enzyme AlkBH₃[J]. Bioorg Med Chem, 2018, 26(14): 4100-4112.
46	Li Q, Huang Y, Liu XC, et al. Rhein inhibits AlkB repair enzymes and sensitizes cells to methylated DNA damage[J]. J Biol Chem, 2016, 291(21): 11083-11093.

[1]	PAERHATI Nadina, ZHANG Pengshan, XU Yitian, CHEN Yunqi, HUANG Chen. Construction of a truncated cylindromatosis tumor suppressor deubiquitinase plasmid and its regulation of the phenotypes of gastric cancer cells [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1149-1160.
[2]	WANG Jingyi, DENG Jiali, ZHU Yi, DING Xinyi, GUO Jiajing, WANG Zhongling. Experimental study on novel pH-responsive manganese-based nanoprobes for ferroptosis and magnetic resonance imaging in breast cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1183-1193.
[3]	YIN Ziming, WANG Rongqin, YANG Ziyi, LIU Yingbin, CHEN Tao, SHU Yijun, GONG Wei. Graph neural network-based auxiliary diagnostic model for gallbladder cancer on CT imaging [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1221-1231.
[4]	JIANG Yi, HUANG Chenhao, LI Zhiliang, WU Junwei, ZHAO Ren, ZHANG Tao. Effect of preoperative chemotherapy combined with immunotherapy in a colorectal cancer patient with KRAS mutation [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1256-1260.
[5]	HUANG Xin, LIU Jiahui, YE Jingwen, QIAN Wenli, XU Wanxing, WANG Lin. Development and clinical application of a machine learning-driven model for metabolite-based diagnosis of small cell lung cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(8): 1009-1016.
[6]	ZHANG Yuqin, AIHEMAITI Yilixiati, WANG Yanli, YANG Zhi, HUANG Jian. Ubiquitination and degradation of RPTPα mediated by MARCH9 [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(8): 957-968.
[7]	AIMAITI Muerzhate, ZHANG Yeqian, LIU Tao, BAI Long, ZHANG Haoyu, NI Bo, GUAN Yujing, WANG Shuchang, GU Jiayi, ZHU Chunchao, XIA Xiang, ZHANG Zizhen. A comparative analysis of the short-term efficacy of robotic and laparoscopic proximal gastrectomy combined with double-flap anastomosis in the treatment of early upper gastric cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(7): 874-882.
[8]	WANG Rui, YUAN Ying, TAO Xiaofeng. Application value of synthetic magnetic resonance imaging in predicting cervical lymph node metastasis of oral cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(7): 900-909.
[9]	YANG Na, LIU Junli, BAI Jing, YANG Siyi, HAN Jiming, ZHANG Huahua. HENMT1 promotes the proliferation and migration of gastric cancer by activating the PI3K-AKT-mTOR signaling pathway [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 717-726.
[10]	TANG Kairan, FENG Chengling, HAN Bangmin. Integrated single-cell and transcriptome sequencing to construct a prognostic model of M2 macrophage-related genes in prostate cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(5): 549-561.
[11]	MAO Chenzhou, ZHANG Ruiyun, CHEN Haige, YIN Fangfei, ZUO Xiaolei. Framework nucleic acid-based linear amplification platform for sensitive detection of bladder cancer-related miRNAs [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(3): 253-260.
[12]	DENG Jiali, GUO Jiajing, WANG Jingyi, DING Xinyi, ZHU Yi, WANG Zhongling. Self -assembled drug -loaded nanoprobes for pyroptosis sensitization and chemical exchange saturation transfer imaging in breast cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(3): 271-281.
[13]	CHEN Jiaying, CHU Yimin, PENG Haixia. Study on prediction model and influencing factors of progression-free survival in colorectal cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(3): 324-334.
[14]	ZOU Peichen, LIU Hongyu, AIHEMAITI· Ayinazhaer, ZHU Liang, TANG Yabin, LEI Huimin. Metabolic profiling of lung cancer cells with acquired resistance to sotorasib [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(2): 138-149.
[15]	CHEN Yongyu, HUANG Yiren, CHEN Zheyi, ZHOU Bingqian, CHEN Shiyu, ZHENG Yingxia. Expression of serpin family E member 1 in gastric cancer and its mechanisms in promoting gastric cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(2): 150-160.