Replication-Dependent Unhooking of DNA Interstrand Cross-Links by the NEIL3 Glycosylase

Semlow, Daniel R.; Zhang, Jieqiong; Budzowska, Magda; Drohat, Alexander C.; Walter, Johannes C.

doi:10.1016/j.cell.2016.09.008

Cited by 170 publications

(238 citation statements)

References 52 publications

(94 reference statements)

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“…Indeed, the nature of DNA incision in the absence of Rad1 is unclear, although structurespecific nucleases such as Slx4, regulated by Slx1, Mus81, and its partner Mms4, and Yen1 have activities that could in principle complement Rad1 loss at some structures (39). Alternatively, new data in Xenopus extracts implicate the N-glycosylase activity of NEIL3, an upstream BER factor, in unhooking psoralen and other ICLs (40). Therefore, it is also possible that yeast N-glycosylases, such as Ntg1 and Ntg2, could act on cisplatin cross-links in the absence of the preferred Rad1 pathway and create a unique chemical moiety that drives slippage-realignment TLS by Polζ in vivo.…”

Section: Discussionmentioning

confidence: 99%

Hypermutation signature reveals a slippage and realignment model of translesion synthesis by Rev3 polymerase in cisplatin-treated yeast

Segovia

Shen

Lujan

et al. 2017

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

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Gene-gene or gene-drug interactions are typically quantified using fitness as a readout because the data are continuous and easily measured in high throughput. However, to what extent fitness captures the range of other phenotypes that show synergistic effects is usually unknown. Using Saccharomyces cerevisiae and focusing on a matrix of DNA repair mutants and genotoxic drugs, we quantify 76 gene-drug interactions based on both mutation rate and fitness and find that these parameters are not connected. Independent of fitness defects, we identified six cases of synthetic hypermutation, where the combined effect of the drug and mutant on mutation rate was greater than predicted. One example occurred when yeast lacking RAD1 were exposed to cisplatin, and we characterized this interaction using whole-genome sequencing. Our sequencing results indicate mutagenesis by cisplatin in rad1Δ cells appeared to depend almost entirely on interstrand cross-links at GpCpN motifs. Interestingly, our data suggest that the following base on the template strand dictates the addition of the mutated base. This result differs from cisplatin mutation signatures in XPF-deficient Caenorhabditis elegans and supports a model in which translesion synthesis polymerases perform a slippage and realignment extension across from the damaged base. Accordingly, DNA polymerase ζ activity was essential for mutagenesis in cisplatin-treated rad1Δ cells. Together these data reveal the potential to gain new mechanistic insights from nonfitness measures of gene-drug interactions and extend the use of mutation accumulation and whole-genome sequencing analysis to define DNA repair mechanisms.mutator | mutation signature | translesion synthesis | gene-drug interaction | DNA repair G enome maintenance pathways suppress the accumulation of mutations derived from chemical lesions or mismatches in DNA that arise during normal metabolic processes. Despite thousands of potentially mutagenic lesions occurring per cell per day, mitotic cell division exhibits extremely low rates of mutation (10

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Section: Discussionmentioning

confidence: 99%

Hypermutation signature reveals a slippage and realignment model of translesion synthesis by Rev3 polymerase in cisplatin-treated yeast

Segovia

Shen

Lujan

et al. 2017

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

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“…AlkZ is one of two DNA glycosylases that unhooks an ICL (16,18). The mechanism by which a DNA glycosylase unhooks an ICL is not immediately obvious, because these enzymes typically capture the modified nucleoside inside the active site by extruding it from the DNA helix, and such a base-flipping mechanism would be inhibited by an ICL.…”

Section: Discussionmentioning

confidence: 99%

“…abasic site-adenine ICLs during DNA replication (18), and that human NEIL1 can excise unhooked psoralen monoadducts and ICLs (19,20). Thus, glycosylase-mediated ICL repair activity has been identified in both prokaryotes and eukaryotes by two distinct proteins.…”

mentioning

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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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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“…In summary, NEIL3 is mainly a monofunctional glycosylase that acts on hydantoins in ssDNA and G4-DNA; however, in G4-DNA the lesion needs to be a located in a relatively large loop. A recent publication found NEIL3 can repair DNA interstrand cross-links; thus, expanding the possible roles NEIL3 has in cells [205]. …”

Section: The Hydantions Are Substrates For Neil2 and Neil3mentioning

confidence: 99%

Formation and processing of DNA damage substrates for the hNEIL enzymes

Fleming

Burrows

2017

Free Radical Biology and Medicine

100

131

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Reactive oxygen species (ROS) are harnessed by the cell for signaling at the same time as being detrimental to cellular components such as DNA. The genome and transcriptome contain instructions that can alter cellular processes when oxidized. The guanine (G) heterocycle in the nucleotide pool, DNA, or RNA is the base most prone to oxidation. The oxidatively-derived products of G consistently observed in high yields from hydroxyl radical, carbonate radical, or singlet oxygen oxidations under conditions modeling the cellular reducing environment are discussed. The major G base oxidation products are 8-oxo-7,8-dihydroguanine (OG), 5-carboxamido-5-formamido-2-iminohydantoin (2Ih), spiroiminodihydantoin (Sp), and 5-guanidinohydantoin (Gh). The yields of these products show dependency on the oxidant and the reaction context that includes nucleoside, single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), and G-quadruplex DNA (G4-DNA) structures. Upon formation of these products in cells, they are recognized by the DNA glycosylases in the base excision repair (BER) pathway. This review focuses on initiation of BER by the mammalian Nei-like1-3 (NEIL1-3) glycosylases for removal of 2Ih, Sp, and Gh. The unique ability of the human NEILs to initiate removal of the hydantoins in ssDNA, bulge-DNA, bubble-DNA, dsDNA, and G4-DNA is outlined. Additionally, when Gh exists in a G4 DNA found in a gene promoter, NEIL-mediated repair is modulated by the plasticity of the G4-DNA structure provided by additional G-runs flanking the sequence. On the basis of these observations and cellular studies from the literature, the interplay between DNA oxidation and BER to alter gene expression is discussed.

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Replication-Dependent Unhooking of DNA Interstrand Cross-Links by the NEIL3 Glycosylase

Cited by 170 publications

References 52 publications

Hypermutation signature reveals a slippage and realignment model of translesion synthesis by Rev3 polymerase in cisplatin-treated yeast

Hypermutation signature reveals a slippage and realignment model of translesion synthesis by Rev3 polymerase in cisplatin-treated yeast

Structure of a DNA glycosylase that unhooks interstrand cross-links

Formation and processing of DNA damage substrates for the hNEIL enzymes

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