Recent progress in the biology, chemistry and structural biology of DNA glycosylases

Schärer, Orlando D.; Jiricny, Josef

doi:10.1002/1521-1878(200103)23:3<270::aid-bies1037>3.0.co;2-j

Cited by 248 publications

(174 citation statements)

References 90 publications

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“…The C-terminal glutamine (Q39), on the other hand, likely plays a catalytic role. Our docking models predict that Q39 protrudes into the minor groove so that its carboxamide side chain is positioned to orient a water nucleophile in the manner observed for N140 in human thymine DNA glycosylase (32) and for aspartate or glutamate side chains in other glycosylases (31). Consistent with such a catalytic role for Q39, approximately one-half of all HTH_42 proteins have an aspartate at this position, suggesting that at least some other members of this previously uncharacterized superfamily also have DNA glycosylase activity.…”

Section: Discussionmentioning

confidence: 87%

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Structure of a DNA glycosylase that unhooks interstrand cross-links

Mullins

Warren

Bradley

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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DNA glycosylases are important editing enzymes that protect genomic stability by excising chemically modified nucleobases that alter normal DNA metabolism. These enzymes have been known only to initiate base excision repair of small adducts by extrusion from the DNA helix. However, recent reports have described both vertebrate and microbial DNA glycosylases capable of unhooking highly toxic interstrand cross-links (ICLs) and bulky minor groove adducts normally recognized by Fanconi anemia and nucleotide excision repair machinery, although the mechanisms of these activities are unknown. Here we report the crystal structure of Streptomyces sahachiroi AlkZ (previously Orf1), a bacterial DNA glycosylase that protects its host by excising ICLs derived from azinomycin B (AZB), a potent antimicrobial and antitumor genotoxin. AlkZ adopts a unique fold in which three tandem winged helix-turn-helix motifs scaffold a positively charged concave surface perfectly shaped for duplex DNA. Through mutational analysis, we identified two glutamine residues and a β-hairpin within this putative DNA-binding cleft that are essential for catalytic activity. Additionally, we present a molecular docking model for how this active site can unhook either or both sides of an AZB ICL, providing a basis for understanding the mechanisms of base excision repair of ICLs. Given the prevalence of this protein fold in pathogenic bacteria, this work also lays the foundation for an emerging role of DNA repair in bacteria-host pathogenesis.

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Section: Discussionmentioning

confidence: 87%

“…S3A), and thus likely in the vicinity of a bound DNA lesion. Monofunctional glycosylases generally initiate nucleophilic attack from the minor groove using carboxylate (Asp, Glu) or carboxamide (Asn, Gln) side chains (31,32). In AlkZ, side chains from conserved glutamines Q37 and Q39 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Structure of a DNA glycosylase that unhooks interstrand cross-links

Mullins

Warren

Bradley

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The cleavage observed herein is indicated by the arrow labeled with an asterisk. (B) The short patch repair pathway involving a monofunctional DNA glycosylase that could generate the cleavage product observed (41). (C) The action of a bifunctional DNA glycosylase͞AP lyase that could generate the cleavage product observed (41).…”

Section: Methodsmentioning

confidence: 99%

Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks

Kress

Thomassin

Grange

2006

Proc. Natl. Acad. Sci. U.S.A.

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Cytosine methylation at CpG dinucleotides contributes to the epigenetic maintenance of gene silencing. Dynamic reprogramming of DNA methylation patterns is believed to play a key role during development and differentiation in vertebrates. The mechanisms of DNA demethylation remain unclear and controversial. Here, we present a detailed characterization of the demethylation of an endogenous gene in cultured cells. This demethylation is triggered in a regulatory region by a transcriptional activator, the glucocorticoid receptor. We show that DNA demethylation is an active process, occurring independently of DNA replication, and in a distributive manner without concerted demethylation of cytosines on both strands. We demonstrate that the DNA backbone is cleaved 3 to the methyl cytidine during demethylation, and we suggest that a DNA repair pathway may therefore be involved in this demethylation.

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“…The major adducts, 7Me G and 3Me A, represent ∼70% of the damage. However, both these methylated bases are efficiently removed from DNA by alkyladenine DNA-glycosylase (Scharer and Jiricny 2001), and the resulting abasic sites are repaired by the BER pathway (Seeberg et al 1995), without causing undue cytotoxicity at low concentrations. Interestingly, the cytotoxicity of the above methylating agents is ascribed to 6Me G, detoxified by methylguanine methyl transferase (MGMT), which reverts it back to guanine (Sedgwick and Lindahl 2002).…”

mentioning

confidence: 99%

Mismatch repair-dependent G₂ checkpoint induced by low doses of S_N1 type methylating agents requires the ATR kinase

Stojic¹,

Mojas²,

Ćejka³

et al. 2004

Genes Dev.

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212

256

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S N 1-type alkylating agents represent an important class of chemotherapeutics, but the molecular mechanisms underlying their cytotoxicity are unknown. Thus, although these substances modify predominantly purine nitrogen atoms, their toxicity appears to result from the processing of O 6 -methylguanine ( 6Me G)-containing mispairs by the mismatch repair (MMR) system, because cells with defective MMR are highly resistant to killing by these agents. In an attempt to understand the role of the MMR system in the molecular transactions underlying the toxicity of alkylating agents, we studied the response of human MMR-proficient and MMR-deficient cells to low concentrations of the prototypic methylating agent N-methyl-N -nitro-N-nitrosoguanidine (MNNG). We now show that MNNG treatment induced a cell cycle arrest that was absolutely dependent on functional MMR. Unusually, the cells arrested only in the second G 2 phase after treatment. Downstream targets of both ATM (Ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) kinases were modified, but only the ablation of ATR, or the inhibition of CHK1, attenuated the arrest. The checkpoint activation was accompanied by the formation of nuclear foci containing the signaling and repair proteins ATR, the S*/T*Q substrate, ␥-H2AX, and replication protein A (RPA). The persistence of these foci implied that they may represent sites of irreparable damage.

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Recent progress in the biology, chemistry and structural biology of DNA glycosylases

Cited by 248 publications

References 90 publications

Structure of a DNA glycosylase that unhooks interstrand cross-links

Structure of a DNA glycosylase that unhooks interstrand cross-links

Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks

Mismatch repair-dependent G₂ checkpoint induced by low doses of S_N1 type methylating agents requires the ATR kinase

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Recent progress in the biology, chemistry and structural biology of DNA glycosylases

Cited by 248 publications

References 90 publications

Structure of a DNA glycosylase that unhooks interstrand cross-links

Structure of a DNA glycosylase that unhooks interstrand cross-links

Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks

Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase

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Mismatch repair-dependent G₂ checkpoint induced by low doses of S_N1 type methylating agents requires the ATR kinase