Review

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

  • Jing-yan HU ,
  • Lin ZHANG ,
  • Liang ZHANG
Expand
  • Department of Pharmacology, Shanghai Jiao Tong University College of Basic Medical Science, Shanghai 200025, China

Online published: 2021-05-27

Supported by

National Natural Science Foundation of China(21722802);Innovative Research Team of High-Level Local Universities in Shanghai(SSMU-ZLCX20180702)

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.

Cite this article

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 Jiao Tong University (Medical Science), 2021 , 41(5) : 684 -689 . DOI: 10.3969/j.issn.1674-8115.2021.05.021

References

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, V?gb? CB, Bj?r?s 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 ?-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 Pil?ys 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.
Outlines

/