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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 ismore » 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.« less

Authors:
 [1];  [1];  [1];  [2];  [1]
  1. New York Univ. (NYU), NY (United States)
  2. New York Univ. (NYU), NY (United States); NYU-ECNU Center for Computational Chemistry, Shanghai (China)
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1543539
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
DNA Repair
Additional Journal Information:
Journal Volume: 65; Journal Issue: C; Journal ID: ISSN 1568-7864
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Genetics & Heredity; Toxicology

Citation Formats

Cai, Yuqin, Fu, Iwen, Geacintov, Nicholas E., Zhang, Yingkai, and Broyde, Suse. 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. United States: N. p., 2018. Web. doi:10.1016/j.dnarep.2018.02.009.
Cai, Yuqin, Fu, Iwen, Geacintov, Nicholas E., Zhang, Yingkai, & Broyde, Suse. 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. United States. doi:10.1016/j.dnarep.2018.02.009.
Cai, Yuqin, Fu, Iwen, Geacintov, Nicholas E., Zhang, Yingkai, and Broyde, Suse. Thu . "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". United States. doi:10.1016/j.dnarep.2018.02.009. https://www.osti.gov/servlets/purl/1543539.
@article{osti_1543539,
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},
author = {Cai, Yuqin and Fu, Iwen and Geacintov, Nicholas E. and Zhang, Yingkai and Broyde, Suse},
abstractNote = {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.},
doi = {10.1016/j.dnarep.2018.02.009},
journal = {DNA Repair},
number = C,
volume = 65,
place = {United States},
year = {2018},
month = {3}
}

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