Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage

Trewick, Sarah C.; Henshaw, Timothy F.; Hausinger, Robert P.; Lindahl, Tomas; Sedgwick, Barbara

doi:10.1038/nature00908

Cited by 721 publications

(659 citation statements)

References 25 publications

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“…For example, it is exciting if some members have DNA modification activity, such as a DNA demethylase. As described above, bacterial AlkB protein, a 2-OG-Fe(II)-dependent dioxygenase, is involved in DNA repair by DNA demethylation (Falnes et al, 2002;Trewick et al, 2002), suggesting the possibility. Because DNA modification as well as histone modification are very important events for making epigenetic signatures, the possibility is very interesting.…”

Section: What Molecular Functions Do Each Jumonji Family Protein or Tmentioning

confidence: 86%

“…The structure of jmjC of HIF1AN/FIH (Elkins et al, 2003) and alignment of the aminoacid sequence of Epe1 and jumonji family proteins suggested that many jumonji family proteins have structures and enzymatic activities similar to those of HIF1AN/FIH. Escherichia coli AlkB family proteins, which remove methyl groups in DNA through oxidative demethylation (Falnes et al, 2002;Trewick et al, 2002), are also 2-OG-Fe (II)-dependent dioxygenases. The above hypothesis was proposed based on analogy of the mechanisms of demethylation by AlkB proteins.…”

Section: Functions Of Jumonji Family Proteins In Transcription and Chmentioning

confidence: 99%

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Roles of jumonji and jumonji family genes in chromatin regulation and development

Takeuchi

Watanabe

Takano-Shimizu

et al. 2006

Developmental Dynamics

177

148

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The jumonji (jmj) gene was identified by a mouse gene trap approach and has essential roles in the development of multiple tissues. The Jmj protein has a DNA binding domain, ARID, and two conserved jmj domains (jmjN and jmjC). In many diverse species including bacteria, fungi, plants, and animals, there are many jumonji family proteins that have only the jmjC domain or both jmj domains. Recently, Jmj protein was found to be a transcriptional repressor. Several proteins in the jumonji family are involved in transcriptional repression and/or chromatin regulation. Most recently, one of the human members has been shown to be a histone demethylase, and the jmjC domain is essential for the demethylase activity. Meanwhile, more and more evidence indicating that the jumonji family proteins play important roles during development is accumulating. Many proteins in the jumonji family may regulate chromatin and gene expression, and control development through various signaling pathways. Here, we highlight the roles of jmj and jumonji family proteins in chromatin regulation and development. Developmental Dynamics 235: 2449 -2459, 2006.

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Section: What Molecular Functions Do Each Jumonji Family Protein or Tmentioning

confidence: 86%

Section: Functions Of Jumonji Family Proteins In Transcription and Chmentioning

confidence: 99%

Roles of jumonji and jumonji family genes in chromatin regulation and development

Takeuchi

Watanabe

Takano-Shimizu

et al. 2006

Developmental Dynamics

177

148

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show abstract

“…However, a reversible tRNA modification process that could noticeably affect gene expression has yet to be shown. FTO and ALKBH5 are RNA demethylases that belong to the human AlkB family dioxygenases that utilize a nonheme iron(II) to catalyze biological oxidation (Falnes et al, 2002;Gerken et al, 2007;Loenarz and Schofield, 2008;Trewick et al, 2002). Almost all of the AlkB family members with known biological functions work on nucleic acid substrates (Fedeles et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

ALKBH1-Mediated tRNA Demethylation Regulates Translation

Liu¹,

Clark²,

Luo³

et al. 2016

Cell

152

190

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SummaryTransfer RNA (tRNA) is a central component of protein synthesis and cell signaling network. One salient feature of tRNA is its heavily modified status, which can critically impact its function. Here we show that mammalian ALKBH1 is a tRNA demethylase. It mediates the demethylation of N 1 -methyladenosine (m 1 A) in tRNAs. The ALKBH1-catalyzed demethylation of the target tRNAs results in attenuated translation initiation and their decreased usage in protein synthesis. This process is dynamic and responds to glucose availability to affect translation. Our results uncover reversible methylation of tRNA as a new regulatory mechanism of post-transcriptional gene expression. In briefReversible tRNA methylation helps translation respond to nutrient availability.

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“…They detected the formation of formaldehyde and showed that the AlkB protein utilizes a previously unknown oxidative demethylation pathway to repair 1-meA and 3-meC DNA damage ( Fig. 1(c)) [30,31]. Thus, in the ada operon both Ada and AlkB use the direct repair pathways to remove methylation DNA damage.…”

mentioning

confidence: 99%

Oxidative dealkylation DNA repair mediated by the mononuclear non-heme iron AlkB proteins

Mishina

2006

Journal of Inorganic Biochemistry

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DNA can be damaged by various intracellular and environmental alkylating agents to produce alkylation base lesions. These base damages, if not repaired promptly, may cause genetic changes that lead to diseases such as cancer. Recently, it was discovered that some of the alkylation DNA base damage can be directly removed by a family of proteins called the AlkB proteins that utilize a mononuclear non-heme iron(II) and α-ketoglutarate as cofactor and cosubstrate. These proteins activate dioxygen and perform an unprecedented oxidative deal-kylation of the alkyl adducts on DNA heteroatoms. This review summarizes the discovery of this activity and the recent research advances in studying this unique DNA repair pathway. The focus is placed on the chemical mechanism and function of these proteins. KeywordsDNA repair; AlkB; ABH; Direct repair; Mononuclear non-heme iron; Dioxygenase; Oxidative dealkylation; Demethylation Direct repair of alkylation DNA damageCellular DNA is subject to nonenzymatic alkylation (methylation) by environmental or chemical mutagens, resulting in adducts that are toxic and mutagenic [1][2][3][4][5][6]. Organisms have evolved a variety of mechanisms to repair these mutagenic damages. Escherichia coli (E. coli) responds to this threat by activating an adaptive responsive pathway, mediated by the E. coli Ada protein [7]. Upon receiving a methyl group from the damaged DNA, Ada turns into a transcriptional activator and activates its own expression and that of the alkB gene and two other genes, alkA and aidB ( Fig. 1(a)) [4,7,8]. The upregulated Ada is a bifunctional protein, which uses a N-terminal Cys38 residue to remove a methyl group fromS p -methylphosphotriester and a C-terminal Cys321 residue to remove a methyl adduct from O 6 -methylguanaine ( Fig. 1(b)) [9][10][11]. Both repair functions are irreversible and represent rare examples of direct repair of DNA damage. AlkA is a glycosylase that cleaves methylated bases from DNA and performs the first step of the well-known base excision repair of base lesions [12][13][14]. The precise function of AidB is still unknown. The function of the last member of this adaptive response, AlkB, also remained unknown until recently despite extensive research efforts. E. coli AlkBSince the first genetic study in 1983 isolating the E. coli mutant with specific sensitivity to the alkylating agent methylmethane sulfonate, MMS [15], the activity of AlkB was undisclosed The Fe II /αKG-dependent dioxygenase superfamily is widespread from bacteria to humans [19] and is the largest known non-heme iron protein family [20][21][22][23]. It represents a wide diversity of enzymes that catalyze the hydroxylation of unactivated C-H groups of a variety of substrates by coupling reductive activation of dioxygen with a decarbox-ylation of αKG, the co-substrate, to succinate. In the event of oxidation one of the oxygen atoms from O 2 is incorporated into the succinate and the other as a hydroxyl in the product [24]. This group of enzymes is known for their importance in ...

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Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage

Cited by 721 publications

References 25 publications

Roles of jumonji and jumonji family genes in chromatin regulation and development

Roles of jumonji and jumonji family genes in chromatin regulation and development

ALKBH1-Mediated tRNA Demethylation Regulates Translation

Oxidative dealkylation DNA repair mediated by the mononuclear non-heme iron AlkB proteins

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