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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)73-78
Number of pages6
JournalDNA Repair
Volume65
DOIs
StatePublished - May 1 2018

Fingerprint

Nucleosomes
DNA Repair
Repair
Nucleotides
Genes
Genome
Histones
Benzo(a)pyrene
DNA
Acetylation
Environmental Carcinogens
Molecular Dynamics Simulation
Transcription
Conformations
Molecular dynamics
Computer simulation

Keywords

  • DNA adduct
  • Histone tails
  • Lysine acetylation
  • MD simulations
  • Nucleosome core particle
  • Nucleotide excision repair

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

@article{fe7d33ea87334e00a1dae1f910b5d86e,
title = "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",
abstract = "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.",
keywords = "DNA adduct, Histone tails, Lysine acetylation, MD simulations, Nucleosome core particle, Nucleotide excision repair",
author = "Yuqin Cai and Iwen Fu and Nicholas Geacintov and Yingkai Zhang and Suse Broyde",
year = "2018",
month = "5",
day = "1",
doi = "10.1016/j.dnarep.2018.02.009",
language = "English (US)",
volume = "65",
pages = "73--78",
journal = "DNA Repair",
issn = "1568-7864",
publisher = "Elsevier",

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TY - JOUR

T1 - Synergistic effects of H3 and H4 nucleosome tails on structure and dynamics of a lesion-containing DNA

T2 - Binding of a displaced lesion partner base to the H3 tail for GG-NER recognition

AU - Cai, Yuqin

AU - Fu, Iwen

AU - Geacintov, Nicholas

AU - Zhang, Yingkai

AU - Broyde, Suse

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

KW - DNA adduct

KW - Histone tails

KW - Lysine acetylation

KW - MD simulations

KW - Nucleosome core particle

KW - Nucleotide excision repair

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U2 - 10.1016/j.dnarep.2018.02.009

DO - 10.1016/j.dnarep.2018.02.009

M3 - Article

VL - 65

SP - 73

EP - 78

JO - DNA Repair

JF - DNA Repair

SN - 1568-7864

ER -