Entrapment of a Histone Tail by a DNA Lesion in a Nucleosome Suggests the Lesion Impacts Epigenetic Marking: A Molecular Dynamics Study

Fu, Iwen; Cai, Yuqin; Zhang, Yingkai; Geacintov, Nicholas E.; Broyde, Suse

doi:10.1021/acs.biochem.5b01166

Cited by 11 publications

(13 citation statements)

References 42 publications

(105 reference statements)

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“…A similar three-component system has recently been modeled with the (+)- trans - anti -BP- N 2 -dGuo DNA adduct and the residues of a histone tail. 39 …”

Section: Discussionmentioning

confidence: 99%

DNA Adduct Formation from Metabolic 5′-Hydroxylation of the Tobacco-Specific Carcinogen N′-Nitrosonornicotine in Human Enzyme Systems and in Rats

Zarth

Upadhyaya

Yang

et al. 2016

Chem. Res. Toxicol.

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N ′-Nitrosonornicotine (NNN) is carcinogenic in multiple animal models and has been evaluated as a human carcinogen. NNN can be metabolized by cytochrome P450s through two activation pathways: 2′-hydroxylation and 5′-hydroxylation. While most previous studies have focused on 2′-hydroxylation in target tissues of rats, available evidence suggests that 5′-hydroxylation is a major activation pathway in human enzyme systems, in non-human primates, and in target tissues of some other rodent carcinogenicity models. In the study reported here, we investigated DNA damage resulting from NNN 5′-hydroxylation by quantifying the adduct 2-(2-(3-pyridyl)-N-pyrrolidinyl)-2′-deoxyinosine (py-py-dI). In rats treated with NNN in the drinking water (7–500 ppm), py-py-dI was the major DNA adduct resulting from 5′-hydroxylation of NNN in vivo. Levels of py-py-dI in lung and nasal cavity were highest, consistent with the tissue distribution of CYP2A3. In rats treated with (S)-NNN or (R)-NNN, the ratios of formation of (R)-py-py-dI to (S)-py-py-dI were not the expected mirror image, suggesting that there may be a carrier for one of the unstable intermediates formed upon 5′-hydroxylation of NNN. Rat hepatocytes treated with (S)- or (R)-NNN or (2′S)- or (2′R)-5′-acetoxyNNN exhibited a pattern of adduct formation similar to live rats. In vitro studies with human liver S9 fraction or human hepatocytes incubated with NNN (2–500 μM) demonstrated that py-py-dI formation was greater than formation of pyridyloxobutyl-DNA adducts resulting from 2′-hydroxylation of NNN. (S)-NNN formed more total py-py-dI adducts than (R)-NNN in human liver enzyme systems, which is consistent with the critical role of CYP2A6 in the 5′-hydroxylation of NNN in human liver. The results of this study demonstrate that the major DNA adduct resulting from NNN metabolism by human enzymes is py-py-dI and provide potentially important new insights on the metabolic activation of NNN in rodents and humans.

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“…A similar three-component system has recently been modeled with the (+)- trans - anti -BP- N 2 -dGuo DNA adduct and the residues of a histone tail. 39 …”

Section: Discussionmentioning

confidence: 99%

DNA Adduct Formation from Metabolic 5′-Hydroxylation of the Tobacco-Specific Carcinogen N′-Nitrosonornicotine in Human Enzyme Systems and in Rats

Zarth

Upadhyaya

Yang

et al. 2016

Chem. Res. Toxicol.

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“…52 Even the presence of a bulky lesion in the DNA near the H2B tail has been simulated to change the tail conformation. 53 Removal of εA at site 96, near the H2B and H4 tails (Figure 5), is significantly inhibited by H3 tail removal but not H2B tail removal. Surprisingly, the shift of the HRF maximum in this region to position 97, making it more OUT, for the gH3 NCP does not enhance εA excision.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Histone tails are essential for formation of nucleosomal arrays through extensive intra- and internucleosomal contacts . Even the presence of a bulky lesion in the DNA near the H2B tail has been simulated to change the tail conformation . Removal of εA at site 96, near the H2B and H4 tails (Figure ), is significantly inhibited by H3 tail removal but not H2B tail removal.…”

Section: Discussionmentioning

confidence: 99%

Nucleosome Core Particles Lacking H2B or H3 Tails Are Altered Structurally and Have Differential Base Excision Repair Fingerprints

Caffrey

Delaney

2021

Biochemistry

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A recently discovered post-translational modification of histone proteins is the irreversible proteolytic clipping of the histone N-terminal tail domains. This modification is involved in the regulation of various biological processes, including the DNA damage response. In this work, we used chemical footprinting to characterize the structural alterations to nucleosome core particles (NCPs) that result from a lack of a histone H2B or H3 tail. We also examine the influence of these histone tails on excision of the mutagenic lesion 1,N 6-ethenoadenine (εA) by the repair enzyme alkyladenine DNA glycosylase. We found that the absence of the H2B or H3 tail results in altered DNA periodicity relative to that of native NCPs. We correlated these structural alterations to εA excision by utilizing a global analysis of 21 εA sites in NCPs and unincorporated duplex DNA. In comparison to native NCPs, there is enhanced excision of εA in tailless H2B NCPs in regions that undergo DNA unwrapping. This enhanced excision is not observed for tailless H3 NCPs; rather, excision is inhibited in more static areas of the NCP not prone to unwrapping. Our results support in vivo observations of alkylation damage profiles and the potential role of tail clipping as a mechanism for overcoming physical obstructions caused by packaging in NCPs but also reveal the potential inhibition of repair by tail clipping in some locations. Taken together, these results further our understanding of how base excision repair can be facilitated or diminished by histone tail removal and contribute to our understanding of the underlying mechanism that leads to mutational hot spots.

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“…The results showed that this base-displaced/intercalated adduct weakens local histone-DNA interactions and causes severe local DNA distortions [41]. Additionally, we have studied a stereoisomerically different B[ a ]P-derived DNA adduct, the 10 S (+)- trans -B[ a ]P- N 2 -dG adduct which resides in the B-DNA minor groove [42]; it was placed at super-helical location (SHL) ~ 3 in the nucleosome environment [43, 44]. In this case, a single nearby histone H2B tail was stably engulfed by the B[ a ]P ring system [43], and upon lysine acetylation of the tail, tail-B[ a ]P interactions were destabilized [44].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, we have studied a stereoisomerically different B[ a ]P-derived DNA adduct, the 10 S (+)- trans -B[ a ]P- N 2 -dG adduct which resides in the B-DNA minor groove [42]; it was placed at super-helical location (SHL) ~ 3 in the nucleosome environment [43, 44]. In this case, a single nearby histone H2B tail was stably engulfed by the B[ a ]P ring system [43], and upon lysine acetylation of the tail, tail-B[ a ]P interactions were destabilized [44]. To further investigate the interactions of histone tails with DNA lesions, here we investigated the well-repaired cis -B[ a ]P-dG DNA adduct [33–35] bracketed by the H3 and H4 tails in a nucleosome with all tails present (PDB [40] ID: 1KX5 [45]), and considered the H4 tail in unacetylated and acetylated states.…”

Section: Introductionmentioning

confidence: 99%

Synergistic effects of H3 and H4 nucleosome tails on structure and dynamics of a lesion-containing DNA: Binding of a displaced lesion partner base to the H3 tail for GG-NER recognition

Cai

Geacintov

et al. 2018

DNA Repair

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How DNA lesions in nucleosomes are recognized for global genome nucleotide excision repair (GG-NER) remains poorly understood, and the roles that histone tails may play remains to be established. Histone H3 and H4 N-terminal tails are of particular interest as their acetylation states are important in regulating nucleosomal functions in transcription, replication and repair. In particular the H3 tail has been the focus of recent attention as a site for the interaction with XPC, the GG-NER lesion recognition factor. Here we have investigated how the structure and dynamics of the DNA lesion cis-B[a]P-dG, derived from the environmental carcinogen benzo[a]pyrene (B[a]P), is impacted by the presence of flanking H3 and H4 tails. This lesion is well-repaired by GG-NER, and adopts a base-displaced/intercalated conformation in which the lesion partner C is displaced into the major groove. We used molecular dynamics simulations to obtain structural and dynamic characterizations for this lesion positioned in nucleosomal DNA so that it is bracketed by the H3 and H4 tails. The H4 tail was studied in unacetylated and acetylated states, while the H3 tail was unacetylated, its state when it binds XPC (Kakumu, Nakanishi et al., 2017). Our results reveal that upon acetylation, the H4 tail is released from the DNA surface; the H3 tail then forms a pocket that induces flipping and capture of the displaced lesion partner base C. This reveals synergistic effects of the behavior of the two tails. We hypothesize that the dual capability of the H3 tail to sense the displaced lesion partner base and to bind XPC could foster recognition of this lesion by XPC for initiation of GG-NER in nucleosomes.

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Entrapment of a Histone Tail by a DNA Lesion in a Nucleosome Suggests the Lesion Impacts Epigenetic Marking: A Molecular Dynamics Study

Cited by 11 publications

References 42 publications

DNA Adduct Formation from Metabolic 5′-Hydroxylation of the Tobacco-Specific Carcinogen N′-Nitrosonornicotine in Human Enzyme Systems and in Rats

DNA Adduct Formation from Metabolic 5′-Hydroxylation of the Tobacco-Specific Carcinogen N′-Nitrosonornicotine in Human Enzyme Systems and in Rats

Nucleosome Core Particles Lacking H2B or H3 Tails Are Altered Structurally and Have Differential Base Excision Repair Fingerprints

Synergistic effects of H3 and H4 nucleosome tails on structure and dynamics of a lesion-containing DNA: Binding of a displaced lesion partner base to the H3 tail for GG-NER recognition

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