Duplex interrogation by a direct DNA repair protein in search of base damage

Yi, Chengqi; Chen, Baoen; Qi, Bo; Zhang, Wen; Jia, Guifang; Zhang, Liang; Li, Charles J.; Dinner, Aaron R.; Yang, Cai‐Guang; He, Chuan

doi:10.1038/nsmb.2320

Cited by 64 publications

(83 citation statements)

References 58 publications

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“…The prominent position of W-433 at the ds/ss junction precludes binding to an intact B-form DNA helix. This residue may be used as a wedge to disrupt the -11 base pair and fill the space vacated by the flipped A −11 , suggesting a functional analogy with other DNA-binding proteins that recognize flipped-out bases using bulky side chains for helix invasion (53,118). Binding of the nontemplate-strand -10 motif to σ 2 introduces a 90 • bend in the DNA backbone that directs the downstream DNA toward the RNAP active site cleft, a prerequisite for subsequent steps of promoter opening and loading of the template strand into the active site (26,28).…”

Section: Strand Separation Of the Dna: The First Step In Formation Ofmentioning

confidence: 99%

Bacterial Sigma Factors: A Historical, Structural, and Genomic Perspective

Feklístov

Sharon

Darst

et al. 2014

Annu. Rev. Microbiol.

426

505

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Transcription initiation is the crucial focal point of gene expression in prokaryotes. The key players in this process, sigma factors (σs), associate with the catalytic core RNA polymerase to guide it through the essential steps of initiation: promoter recognition and opening, and synthesis of the first few nucleotides of the transcript. Here we recount the key advances in σ biology, from their discovery 45 years ago to the most recent progress in understanding their structure and function at the atomic level. Recent data provide important structural insights into the mechanisms whereby σs initiate promoter opening. We discuss both the housekeeping σs, which govern transcription of the majority of cellular genes, and the alternative σs, which direct RNA polymerase to specialized operons in response to environmental and physiological cues. The review concludes with a genome-scale view of the extracytoplasmic function σs, the most abundant group of alternative σs.

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Section: Strand Separation Of the Dna: The First Step In Formation Ofmentioning

confidence: 99%

Bacterial Sigma Factors: A Historical, Structural, and Genomic Perspective

Feklístov

Sharon

Darst

et al. 2014

Annu. Rev. Microbiol.

426

505

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“…ALKBH2 uses several active-site residues to recognize 1-meA and uses an aromatic finger residue Phe102 to facilitate base flipping ). In addition, Phe102 can also probe the stability of base pairs when ALKBH2 is interrogating DNA for damage; the unique oxidation chemistry of ALKBH2 then ensures that only a cognate substrate will be modified (Yi et al 2012). It remains to be seen if ALKBH2 could signal or recruit additional repair factors when it encounters noncognate damage (Gilljam et al 2009).…”

Section: Alkbh1: Ap Lyase or Demethylase?mentioning

confidence: 99%

“…5A). Using a disulfide cross-linking technique, we have succeeded in the structural characterization of ALKBH2 bound to duplex DNA containing different base lesions Yi et al 2012). ALKBH2 uses several active-site residues to recognize 1-meA and uses an aromatic finger residue Phe102 to facilitate base flipping ).…”

Section: Alkbh1: Ap Lyase or Demethylase?mentioning

confidence: 99%

DNA Repair by Reversal of DNA Damage

2013

Cold Spring Harbor Perspectives in Biology

133

115

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Endogenous and exogenous factors constantly challenge cellular DNA, generating cytotoxic and/or mutagenic DNA adducts. As a result, organisms have evolved different mechanisms to defend against the deleterious effects of DNA damage. Among these diverse repair pathways, direct DNA-repair systems provide cells with simple yet efficient solutions to reverse covalent DNA adducts. In this review, we focus on recent advances in the field of direct DNA repair, namely, photolyase-, alkyltransferase-, and dioxygenase-mediated repair processes. We present specific examples to describe new findings of known enzymes and appealing discoveries of new proteins. At the end of this article, we also briefly discuss the influence of direct DNA repair on other fields of biology and its implication on the discovery of new biology. E ndogenous and environmental agents continuously threaten the genomic integrity of all living organisms. Replication of damaged DNA can lead to mutations that are tumorigenic, whereas DNA lesions that block replication or transcription can result in senescence and cell death. Therefore, cellular DNA must be promptly repaired. Well-known mechanisms include base-excision repair, nucleotide excision repair, mismatch repair, homologous recombination, and nonhomologous end joining. In addition, nature has also evolved several mechanisms in which the damage is directly reversed most often by a single repair protein without the incision of DNA backbone. Although such "direct repair" processes mediate the reversal of a relatively small set of DNA lesions, the simplicity and essentially error-free property of the direct reversal processes make them particularly attractive for a cell. Three major mechanisms of direct DNA repair have been identified to date: (i) photolyases reverse UV light-induced photolesions; (ii) O 6 -alkylguanine-DNA alkyltransferases (AGTs) reverse a set of O-alkylated DNA damage; and (iii) the AlkB family dioxygenases reverse N-alkylated base adducts (Fig. 1). This concise article intends to update knowledge since the publication of the second edition of DNA Repair and Mutagenesis (ASM) (Friedberg et al. 2006).

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“…The housekeeping enzyme in mammalian cells, ALKBH2, plays a crucial role in pediatric brain tumors during chemotherapy treatment (20). Essential for prostate cancer progression, ALKBH3 presents a potential target for effective therapy in prostate cancer (21,22).Structural characterizations of AlkB repair enzymes have provided insights into the understanding of demethylation mechanism and substrate recognition (23)(24)(25)(26). Similar to members of the 2OG-dioxygenase family, 2OG could inhibit AlkB at high concentrations (27).…”

mentioning

confidence: 99%

“…Structural characterizations of AlkB repair enzymes have provided insights into the understanding of demethylation mechanism and substrate recognition (23)(24)(25)(26). Similar to members of the 2OG-dioxygenase family, 2OG could inhibit AlkB at high concentrations (27).…”

mentioning

confidence: 99%

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

Huang

Liu

et al. 2016

Journal of Biological Chemistry

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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.The nucleic acids in living cells are subject to modification by both endogenous and environmental agents (1). Direct-acting chemicals constantly damage nucleic acids and generate various methyl lesions with mutagenic and/or cytotoxic consequences (2, 3). O 6 -Methylguanine (O 6 mG) 2 and N 3 -methyladenine lesions have the highest potential for methylating damage by an SN1 agent such as N-methyl-NЈ-nitro-N-nitrosoguanidine (MNNG), which block replication and are thought to be toxic (4, 5). For the most part, the SN2 agent such as methyl methane sulfonate (MMS) produces N 1 -methyladenine (m 1 A) and N 3 -methylcytosine (m 3 C) lesions in single-stranded DNA (ssDNA). Accumulation of these adducts can lead to cell death (6, 7). Organisms have evolved several mechanisms to efficiently remove various methyl lesions, including suicidal methyltransferases, DNA glycosylases, and the AlkB family dioxygenases (see Fig. 1A) (8, 9). To date, AlkB repair appears to be the major natural defense mechanism with the power to restore the canonical base structure in vivo. Escherichia coli AlkB and its human homologues, ALKBH2 and ALKBH3, utilize iron(II) and 2-oxoglutarate (2OG) to achieve oxidative demethylation of m 1 A and m 3 C (see Fig. 1B) (10 -12). The lack of AlkB repair results in increased sensitivity to MMS, elevated level of mutations, and reduced cell proliferation (13-16). Furthermore, the accumulation of m 1 A and m 3 C lesions could also occur on RNA. Research suggests that the oxidative demethylation in mRNA and tRNA acts as a part of AlkB or ALKBH3 repair to protect cells against MMS (17, 18). The scope of substrates for AlkB repair has been largely extended to all simple N-alkyl lesions at the WatsonCrick base-pairing interface on the four bases (19), thus indicating the importance of oxidative demethylation for cell survival. In addition, human enzymes have been broadly linked to cancer. The housekeeping ...

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Duplex interrogation by a direct DNA repair protein in search of base damage

Cited by 64 publications

References 58 publications

Bacterial Sigma Factors: A Historical, Structural, and Genomic Perspective

Bacterial Sigma Factors: A Historical, Structural, and Genomic Perspective

DNA Repair by Reversal of DNA Damage

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

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