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Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage. 2016

Qi Li, and Yue Huang, and Xichun Liu, and Jianhua Gan, and Hao Chen, and Cai-Guang Yang
From the Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

The AlkB repair enzymes, including Escherichia coli AlkB and two human homologues, ALKBH2 and ALKBH3, are iron(II)- and 2-oxoglutarate-dependent dioxygenases that efficiently repair N(1)-methyladenine and N(3)-methylcytosine methylated DNA damages. The development of small molecule inhibitors of these enzymes has seen less success. Here we have characterized a previously discovered natural product rhein and tested its ability to inhibit AlkB repair enzymes in vitro and to sensitize cells to methyl methane sulfonate that mainly produces N(1)-methyladenine and N(3)-methylcytosine lesions. Our investigation of the mechanism of rhein inhibition reveals that rhein binds to AlkB repair enzymes in vitro and promotes thermal stability in vivo In addition, we have determined a new structural complex of rhein bound to AlkB, which shows that rhein binds to a different part of the active site in AlkB than it binds to in fat mass and obesity-associated protein (FTO). With the support of these observations, we put forth the hypothesis that AlkB repair enzymes would be effective pharmacological targets for cancer treatment.

UI MeSH Term Description Entries
D008741 Methyl Methanesulfonate An alkylating agent in cancer therapy that may also act as a mutagen by interfering with and causing damage to DNA. Methylmethane Sulfonate,Dimethylsulfonate,Mesilate, Methyl,Methyl Mesylate,Methyl Methylenesulfonate,Methylmesilate,Mesylate, Methyl,Methanesulfonate, Methyl,Methyl Mesilate
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D011994 Recombinant Proteins Proteins prepared by recombinant DNA technology. Biosynthetic Protein,Biosynthetic Proteins,DNA Recombinant Proteins,Recombinant Protein,Proteins, Biosynthetic,Proteins, Recombinant DNA,DNA Proteins, Recombinant,Protein, Biosynthetic,Protein, Recombinant,Proteins, DNA Recombinant,Proteins, Recombinant,Recombinant DNA Proteins,Recombinant Proteins, DNA
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006899 Mixed Function Oxygenases Widely distributed enzymes that carry out oxidation-reduction reactions in which one atom of the oxygen molecule is incorporated into the organic substrate; the other oxygen atom is reduced and combined with hydrogen ions to form water. They are also known as monooxygenases or hydroxylases. These reactions require two substrates as reductants for each of the two oxygen atoms. There are different classes of monooxygenases depending on the type of hydrogen-providing cosubstrate (COENZYMES) required in the mixed-function oxidation. Hydroxylase,Hydroxylases,Mixed Function Oxidase,Mixed Function Oxygenase,Monooxygenase,Monooxygenases,Mixed Function Oxidases,Function Oxidase, Mixed,Function Oxygenase, Mixed,Oxidase, Mixed Function,Oxidases, Mixed Function,Oxygenase, Mixed Function,Oxygenases, Mixed Function
D000071499 AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase A dioxygenase and alkylation repair homolog that repairs alkylated DNA and RNA containing 1-methyladenine and 3-methylcytosine by oxidative demethylation. It can also repair alkylated DNA containing 1-ethenoadenine in vitro. It has highest affinity for double-stranded DNA. Alkylated DNA Repair Protein AlkB Homolog 2,Alpha-ketoglutarate-Dependent Dioxygenase AlkB Homolog 2,DNA Oxidative Demethylase ALKBH2,Oxy DC1 Protein,AlkB Homolog 2, Alpha Ketoglutarate Dependent Dioxygenase,Alpha ketoglutarate Dependent Dioxygenase AlkB Homolog 2
D000071500 AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase A dioxygenase and alkylation repair homolog that repairs alkylated DNA containing 1-methyladenine (1meA) and 3-methylcytosine (3meC) by oxidative demethylation. It has a strong preference for SINGLE-STRANDED DNA and may also act on RNA. Alkylated DNA Repair Protein AlkB Homolog 3,Alpha-Ketoglutarate-Dependent Dioxygenase AlkB Homolog 3,Prostate Cancer Antigen 1,AlkB Homolog 3, Alpha Ketoglutarate Dependent Dioxygenase,Alpha Ketoglutarate Dependent Dioxygenase AlkB Homolog 3

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