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Chapter 5 : Reversal of Alkylation Damage in DNA

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Reversal of Alkylation Damage in DNA, Page 1 of 2

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Abstract:

In addition to the repair of various photoproducts by one-step enzymatic reactions that directly reverse base damage, nature employs other forms of direct reversal for the repair of at least four types of alkylation base damage in DNA. This chapter considers the DNA repair by enzyme-catalyzed reversal of , , , and . Before concluding our discussions of the repair of DNA damage by direct reversal, it is relevant to include the rejoining of single-strand breaks in DNA specifically with and . At least in and possibly in other organisms as well, some of the single-strand breaks in DNA produced by ionizing radiation under anoxic conditions are repaired by simple rejoining of the ends (70), and such repair may be considered an example of the direct reversal of DNA damage.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5

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Figures

Image of Figure 5–1
Figure 5–1

Adaptation to cell killing and to mutagenesis in A culture of cells mutant for tryptophan metabolism (trp) was grown for 90 min in the presence of various small amounts of MNNG (adapting doses). At the end of this time, samples were exposed to a much larger dose of MNNG for 5 min (challenging dose) and the surviving fraction and reversion frequency were determined. In adapted cells, survival increased and mutation frequency (normalized to survival) decreased.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–2
Figure 5–2

Preferential loss of -methylguanine from the DNA of adapted cells. cells were exposed to either adapting or nonadapting conditions and then challenged with a larger dose of radiolabeled alkylating agent. Following a period of incubation, DNA from both groups of cells was isolated and hydrolyzed. The alkylated bases 3-methyladenine (3-meA), 7-methylguanine (7-meG), and methylguanine ( -meG) in the hydrolysate were identified by chro-matographic separation.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–3
Figure 5–3

An enzyme activity called -AGT transfers a methyl group from the O position of guanine in DNA to a cysteine residue in the protein, thereby restoring the native chemistry of guanine and repairing the base damage by direct reversal. MeG, -methylguanine.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–4
Figure 5–4

Chromatographic analysis following enzymatic hydrolysis of poly(dC-dG[8-H] -MeG) incubated with extracts of nonadapted (top) and adapted (bottom) cells. Note the presence of demethylated dG in the latter. -MeG, -methylguanine. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–5
Figure 5–5

The O position of guanine (bottom) and the O position of thymine (top diagram) project into the major groove of the B-form DNA double helix. Other sites of alkylation, such as N-3 adenine (top), N-3 guanine (bottom), and O-cytosine (bottom), project into the minor groove. (Adapted from Friedberg et al. [ ].)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–6
Figure 5–6

Schematic representation of the (left) and Sp (right) stereoisomers of methylphosphotriesters produced by the alkylation of phosphate residues in DNA. B and B connote bases in DNA. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–7
Figure 5–7

The Ada protein N-terminal domain. The diagram shows superimposed NMR structures of the 10-kDa Nterminal domain of Ada that catalyzes the transfer of a methyl group from a DNA methylphosphotriester to Cys38 of the Ada protein. The grey sphere represents a Zn atom coordinated by multiple cysteine residues.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–8
Figure 5–8

Acceptor cysteine residues in the Ada protein involved in removal of simple alkyl groups from DNA. The 354-amino-acid Ada polypeptide (top) is represented to show the 12 cysteine residues in the polypeptide and the relative positions of Cys38 (in the N-terminal half) and Cys321 (in the C-terminal half), separated by a central hinge region. Amino acids (E, K, and R) constitute sites that are particularly sensitive to endogenous cleavage of the polypeptide. The N-terminal and C-terminal domains are represented diagrammatically below to show abstraction of methyl groups from phosphotriesters (left) and O-alkylguanine (right). (Adapted from references and .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–9
Figure 5–9

The Cys321 active-site region of the Ada protein ( -AGT I) and those of thymidylate synthase from various sources. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–10
Figure 5–10

The zinc finger domain (Cys-X-Cys-X-Cys-X-Cys) of Ada protein is located in the N-terminal domain of the protein. Amino acid sequences in this region are conserved in the proteins from serovar Typhimurium and Identical amino acids in all three polypeptides (in addition to the conserved cysteines) are highlighted. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–11
Figure 5–11

Regulation of the adaptive response to alkylating agents. The Ada regulon, consisting of the gene as well as the and genes (see chapter 6), is shown. The “ada boxes” in the promoters of the operon and the gene are also indicated, and the polypeptides encoded by these genes are shown schematically. The polypeptide encoded by the gene is represented to show the N-terminal and C-terminal domains containing receptor cysteine residues for alkyl groups (see the text for details). Following the exposure of cells to methylating agents, DNA is alkylated at several sites, including the O position of guanine, the O position of thymine, and phosphate residues in the sugar-phosphate backbone, to form phosphotriesters. Ada protein catalyzes the transfer of methyl groups from phosphotriesters to the N-terminal cysteine (Cys38) and from -alkylguanine or O-alkylthymine to the C-terminal cysteine (Cys321). The Cys38 alkylation converts the protein to a transcriptional activator that binds to the promoters of genes in the Ada regulon, resulting in enhanced transcription. The increased levels of Ada protein and of the products of the other genes (see chapter 6) promote enhanced repair of alkylation damage in DNA. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–12
Figure 5–12

Conservation of amino acid residues around the active site of the Ada N-terminal domain. Many of the residues surrounding the zinc-binding site of the Ada protein 10-kDa Nterminal domain are conserved. These include four cysteines that coordinate the zinc atom (Cys38, Cys42, Cys69, and Cys72) and Thr34, Gly35, Asn51, Phe66, Arg67, Lys70, and Arg71. These conserved residues probably participate in the abstraction of a methyl group from DNA methylphosphotriesters and/or activation of transcription at promoters that are subject to regulation by Ada protein during the adaptive response to alkylating agents.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–13
Figure 5–13

Docking model of the Ada protein N-domain bound to DNA. The N-terminal domain of the Ada protein selectively reacts with the stereoisomer of methylphosphotriesters, transferring the methyl group from DNA to Cys38 and converting Ada to a transcriptional activator. The theoretical DNA-docking model shown here positions many of the conserved residues (see Fig. 5–11 ) at the DNA-binding interface and suggests the basis for the stereoselectivity of methyl transfer. The methyl group faces the Ada zinc thiolate cluster, whereas the methyl isomer of a methylphosphotriester would point away from the Ada protein.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–14
Figure 5–14

The promoter contains an “Ada box” (highlighted) in a region of dyad symmetry (arrows).

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–15
Figure 5–15

Ada protein has two distinct methyltransferase activities. The N-terminal domain abstracts methyl groups from DNA methylphosphotriesters, whereas the 19-kDa Cterminal domain of Ada shown here is an -methylguanine methyltransferase. In both reactions a methyl group is irreversibly transferred from DNA to a cysteine residue. The Ada C-terminal domain has a bilobed structure consisting of two subdomains with the conserved active-site residues located in a cleft between them. The structure of the N-terminal subdomain resembles that of RNase H, and the C-terminal subdomain is α-helical. The structure of human -alkylguanine DNA alkyltransferase closely resembles that of the Ada C-terminal domain, suggesting common mechanisms for the prokaryotic and eukaryotic enzymes. The bilobed structures of the Ada C-terminal domain and the human AGT are reminiscent of the helix-hairpin-helix DNA glycosylases (see chapter 6), which gain access to bases in double-stranded DNA by base flipping, suggesting a means for accessing the -methylguanine substrate in double-stranded DNA.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–16
Figure 5–16

Diagrammatic representation of regions of amino acid sequence homology in the N- and C-terminal regions of seven -alkylguanine-DNA methyltransferase proteins. These are -AGT I and -AGT II of the AdaA, AdaB, and Dat1 proteins of Ada protein of serovar Typhimurium, and MGT1 protein of the yeast The alkylacceptor cysteine residues are identified in each case. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–17
Figure 5–17

Conservation of the amino acid sequence in the C-terminal regions of -AGT from prokaryotes and eukaryotes. Amino acids are numbered according to the rat polypeptide (top line). The active cysteine residue corresponding to Cys321 in AGT protein is highlighted in dark gold. serovar Typhimurium;

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–18
Figure 5–18

(A) MNNG-induced mutagenesis in double-mutant and single-mutant strains. cells () were treated with MNNG and plated on minimal plates lacking histidine (to quantitate his revertants) and on minimal plates supplemented with histidine (to quantitate survivors). (B) Spontaneous mutagenesis in various single and double and mutants. cells () were plated on minimal plates containing very small amounts of histidine and incubated at 37°C. Revertants (his) were scored daily. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–19
Figure 5–19

Bisulfite sequencing (which measures methylated cytosine by conversion to thymine) in the CpG island of the promoter in human Mer+ (top) and Mer (bottom) cell lines. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–20
Figure 5–20

Model for the aberrant silencing of the CpG island-containing gene in mammalian cells. (A) In Mer cells, gene expression is associated with a nucleosome-free region of transcription factor (represented by the inverted teardrop structures) binding that is surrounded by at least four positioned nucleosome-like structures (five are shown in the cartoon). (B) In Mer cells, silencing is associated with a loss of nucleosome positioning and exclusion of transcription factor binding. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–21
Figure 5–21

Correlation between enhancer activity and endogenous levels of -MGMT activity in various Mer cell lines. Activity was measured by transiently transfecting cells with a reporter gene containing the minimal promoter and an enhancer sequence. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–22
Figure 5–22

Modulation of expression in human cells by phorbol-12-myristate-13-acetate (TPA) and 1,2-diacyl--glycerol (DAG). The black lines represent treated cells and the gold lines represent untreated cells. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–23
Figure 5–23

Functional complementation of an mutant strain by a human homolog of the bacterial gene, Shown are survival levels for cells (grey), mutant cells transformed with the gene (black), mutant cells transformed with an empty vector (dark gold), and mutant cells transformed with the human gene (lighter gold). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–24
Figure 5–24

Defective reactivation of single-stranded phages treated with MMS in an mutant (black lines). The phages used were M13, f1, and G4 (shown in separate panels). Reactivation in an strain is indicated by the gold survival curves. No reactivation of the MMS-treated double-stranded phage λ is observed. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–25
Figure 5–25

The numbering of the pyrimidine ring in purine (dAMP) and pyrimidine (dTMP) nucleotides is different.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–26
Figure 5–26

Topological diagrams for three members of the 2-oxoglutarate and Fe(II)-dependent oxygenase family. The diagrams are based on experimentally determined structures for isopenicillin N synthase from and from structural models of prolyl-4-hydroxylase and AlkB proteins. Amino acid residues in the active site are indicated schematically in gold, as is the Fe(II) ion (black dots). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–27
Figure 5–27

The repair of N-methyladenine (1-MeA) and N-methylcytosme (3-MeC) by AlkB protein (A and B). The N-1 and N-3 positions of adenine and cytosine are equivalent in the sense that in single-stranded DNA they are both susceptible to attack by methylating agents (A) whereas in double-stranded DNA they are shielded from such attack (B). Both 1MeA and 3MeC lesions can be generated in regions of single-stranded DNA and on reannealing of the double helix these lesions persist. The lesions are buried within the double helix of DNA but are expected to disrupt hydrogen bonding with the complementary strand (broken gold lines) (B). (C andD) Both 1MeA and 3MeC in DNA are repaired by AlkB-catalyzed oxidative demethylation. The reaction requires α-ketoglutarate, O and Fe and generates succinate and CO. (E) The oxidized methyl groups are removed as formaldehyde, regenerating normal DNA bases. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–28
Figure 5–28

Alignment of AlkB, ABH1 (human AlkB homolog 1) ABH2 (human AlkB homolog 2), and ABH3 (human AlkB homolog 3) amino acid sequences. Only identical amino acids are shown. Arrows indicate residues in the presumed Fe-binding cluster. An Arg residue thought to be involved in binding 2-oxoglutarate is indicated by the asterisk. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–29
Figure 5–29

Reversal of alkylation damage in RNA and DNA by AlkB protein of and by human ABH2 and human ABH3 proteins. (A) Reverse-phase high-performance liquid chromatography analysis of H-methylated nucleosides in DNA and RNA homopolymers incubated in the absence (black lines) or presence (gold lines) of AlkB (top), ABH2 (middle), and ABH3 (bottom). Arrows indicate the identity of H-methylated nucleosides in the peaks based on coelution with internal standards [M1(dA), M3(dC), M1A, and M3C]. (B) Comparison of activity on single-stranded (ss) and double-stranded (ds) oligonucleotides. AlkB (left), ABH2 (center), and ABH3 (right) were incubated with a Hmethylated A-rich oligonucleotide (ss-oligo) or with the same oligonucleotide associated with its unmethylated complementary strand (ds-oligo), and ethanol-soluble radioactivity was measured. (C) Activity of AlkB (left), ABH2 (center), and ABH3 (right) on the H-methylated substrates M13 single-stranded DNA, poly(dA), poly(dC), poly(A), and poly(C). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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Image of Figure 5–30
Figure 5–30

DNA ligase catalyzes the joining of strand breaks that contain juxtaposed 3’-OH or 5’P-termini in DNA. The enzyme from requires NAD as a cofactor; that encoded by phage T4 requires ATP.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Reversal of Alkylation Damage in DNA, p 139-168. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch5
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References

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