The C-terminal Domain (CTD) of Human DNA Glycosylase NEIL1 Is Required for Forming BERosome Repair Complex with DNA Replication Proteins at the Replicating Genome

Hegde, Pavana M.; Dutta, Arijit; Sengupta, Shiladitya; Mitra, Joy; Adhikari, Sanjay; Tomkinson, Alan E.; Li, Guo Min; Boldogh, István; Hazra, Tapas K.; Mitra, Sankar; Hegde, Muralidhar L.

doi:10.1074/jbc.m115.642918

Cited by 43 publications

(56 citation statements)

References 48 publications

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“…Additional NEIL1 interactions occur with the DNA repair proteins PNK, POLβ, XRCC1, and LIGIII [212], via the C-terminal domain (Fig. 5C) [213]. Furthermore, NEIL1 deficiency slows replication fork progression in oxidatively stressed cells [214].…”

Section: The Biology Of the Neils And Hydantoinsmentioning

confidence: 99%

Formation and processing of DNA damage substrates for the hNEIL enzymes

Fleming

Burrows

2017

Free Radical Biology and Medicine

100

135

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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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Section: The Biology Of the Neils And Hydantoinsmentioning

confidence: 99%

Formation and processing of DNA damage substrates for the hNEIL enzymes

Fleming

Burrows

2017

Free Radical Biology and Medicine

100

135

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“…The N terminus contains the glycosylase domain of NEIL1, and the C terminus is intrinsically disordered (8,11). Whereas the C terminus is dispensable for both glycosylase and lyase activities in vitro, it interacts with many proteins in vivo and is required for efficient DNA repair activity inside the cells (12,13). NEIL1 is also unique among the three human NEIL proteins in that it is increased in an S-phase-specific manner and carries out prereplicative repair of oxidized bases in the human genome (8,12).…”

mentioning

confidence: 99%

Tautomerization-dependent recognition and excision of oxidation damage in base-excision DNA repair

Zhu

Zhang

et al. 2016

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

119

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NEIL1 (Nei-like 1) is a DNA repair glycosylase guarding the mammalian genome against oxidized DNA bases. As the first enzymes in the base-excision repair pathway, glycosylases must recognize the cognate substrates and catalyze their excision. Here we present crystal structures of human NEIL1 bound to a range of duplex DNA. Together with computational and biochemical analyses, our results suggest that NEIL1 promotes tautomerization of thymine glycol (Tg)-a preferred substrate-for optimal binding in its active site. Moreover, this tautomerization event also facilitates NEIL1-catalyzed Tg excision. To our knowledge, the present example represents the first documented case of enzymepromoted tautomerization for efficient substrate recognition and catalysis in an enzyme-catalyzed reaction.base-excision repair | substrate recognition | enzyme catalysis | glycosylase | QM/MM D NA oxidation damage can be induced by both endogenous and environmental reactive oxygen species. Such oxidized DNA bases are primarily recognized and removed by the baseexcision repair (BER) pathway, which is initiated by a lesionspecific DNA glycosylase (1-4). Based on sequence homology and structural motifs, glycosylases that cleave oxidation damage are grouped into two families: the helix-hairpin-helix (HhH) family and the Fpg/Nei family (5, 6); the latter is named after the prototypical bacterial members formamidopyrimidine DNA glycosylase (Fpg) and endonuclease eight (Nei).NEIL1 (Nei-like 1) is one such Fpg/Nei family glycosylase that guards the mammalian genome against oxidation damage (7-10). NEIL1 is bifunctional in that it catalyzes both the hydrolysis of the N-glycosylic bond linking a base to a deoxyribose (glycosylase activity) and the subsequent cleavage of the DNA 3′ to the newly created apurinic/apyrimidinic site (lyase activity) (7-10). The N terminus contains the glycosylase domain of NEIL1, and the C terminus is intrinsically disordered (8,11). Whereas the C terminus is dispensable for both glycosylase and lyase activities in vitro, it interacts with many proteins in vivo and is required for efficient DNA repair activity inside the cells (12, 13). NEIL1 is also unique among the three human NEIL proteins in that it is increased in an S-phase-specific manner and carries out prereplicative repair of oxidized bases in the human genome (8,12). Moreover, increasing literature has further emphasized the importance of NEIL1's cellular repair activity, as NEIL1 deficiency has led to multiple abnormalities and is associated with severe human diseases, including cancer (14-19). Additionally, emerging evidence has also implicated a role of NEIL1 in active DNA demethylation (20)(21)(22).NEIL1 is capable of removing a wide array of oxidized pyrimidines and purines; representative substrates of extensive investigations include thymine glycol (Tg), 5-hydroxyuracil (5-OHU), 5-hydroxycytosine (5-OHC), dihydrothymine (DHT), and dihydrouracil (DHU), as well as the formamidopyridines (FapyA and FapyG), spiroiminodihydantoin (Sp), and guanidinohydanto...

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“…Participants were judged on similarity of the model structure within the region that crystallized. Although SAXS has the potential to provide restraints for computational algorithms, the SAXS data collected was complicated by a high level of flexibility in the targets and/or multimerization. Modelers needed to include this information, in order to generate models that matched the SAXS data.…”

Section: Discussionmentioning

confidence: 99%

“…Flexible regions are often required for stability and solubility, as seen for NEIL1. 47,48 Ignoring multimerization is potentially disregarding contacts that may be just as important for folding as those made within the peptide itself and could thus mislead protein algorithms to identify surfaces that are exposed in subunits but buried in the solution state assembly as Given the value for including some monomeric globular targets and stoichiometrically monodisperse samples, the following strategies for SAXS data collection and analysis are suggested to improve target data for predictors. First, priority should be given to identify proteins with low percentages of residues missing from the crystal structure and those whose biological unit is predicted to be monomeric.…”

Section: Discussionmentioning

confidence: 99%

Small angle X‐ray scattering and cross‐linking for data assisted protein structure prediction in CASP 12 with prospects for improved accuracy

et al. 2018

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Experimental data offers empowering constraints for structure prediction. These constraints can be used to filter equivalently scored models or more powerfully within optimization functions toward prediction. In CASP12, Small Angle X-ray Scattering (SAXS) and Cross-Linking Mass Spectrometry (CLMS) data, measured on an exemplary set of novel fold targets, were provided to the CASP community of protein structure predictors. As solution-based techniques, SAXS and CLMS can efficiently measure states of the full-length sequence in its native solution conformation and assembly. However, this experimental data did not substantially improve prediction accuracy judged by fits to crystallographic models. One issue, beyond intrinsic limitations of the algorithms, was a disconnect between crystal structures and solution-based measurements. Our analyses show that many targets had substantial percentages of disordered regions (up to 40%) or were multimeric or both. Thus, solution measurements of flexibility and assembly support variations that may confound prediction algorithms trained on crystallographic data and expecting globular fully-folded monomeric proteins. Here, we consider the CLMS and SAXS data collected, the information in these solution measurements, and the challenges in incorporating them into computational prediction. As improvement opportunities were only partly realized in CASP12, we provide guidance on how data from the full-length biological unit and the solution state can better aid prediction of the folded monomer or subunit. We furthermore describe strategic integrations of solution measurements with computational prediction programs with the aim of substantially improving foundational knowledge and the accuracy of computational algorithms for biologically-relevant structure predictions for proteins in solution.

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The C-terminal Domain (CTD) of Human DNA Glycosylase NEIL1 Is Required for Forming BERosome Repair Complex with DNA Replication Proteins at the Replicating Genome

Cited by 43 publications

References 48 publications

Formation and processing of DNA damage substrates for the hNEIL enzymes

Formation and processing of DNA damage substrates for the hNEIL enzymes

Tautomerization-dependent recognition and excision of oxidation damage in base-excision DNA repair

Small angle X‐ray scattering and cross‐linking for data assisted protein structure prediction in CASP 12 with prospects for improved accuracy

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