Nucleosomes and Epigenetics from a Chemical Perspective

Feng, Yihong; Endo, Masayuki; Sugiyama, Hiroshi

doi:10.1002/cbic.202000332

Cited by 9 publications

(10 citation statements)

References 148 publications

(163 reference statements)

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“…These newly discovered modifications are defined as nonenzymatic covalent histone modifications and have attracted increasing attention . Existing techniques, such as chromatin immunoprecipitation, followed by sequencing (ChIP–seq) and chromosome conformation capture (3C), may be employed to probe and map these nonenzymatic histone modifications in vivo. , Developing additional platforms for such a purpose requires urgent attention . Finally, how these new lesions influence chromatin structure and how they modulate DNA replication, transcription, repair, and epigenetic regulation in eukaryotic cells needs to be investigated.…”

Section: Discussionmentioning

confidence: 89%

“…87,88 Developing additional platforms for such a purpose requires urgent attention. 24 Finally, how these new lesions influence chromatin structure and how they modulate DNA replication, transcription, repair, and epigenetic regulation in eukaryotic cells needs to be investigated. Research in this area may facilitate the development of new therapies targeting nucleosomes and chromatin.…”

Section: Discussionmentioning

confidence: 99%

“…In the past decade, we and others have developed a strategy for delineating how histones modulate DNA damage and repair chemistry in reconstituted nucleosome core particles (NCPs, nucleosomes lacking linker DNA). − To this end, a series of DNA lesions and reactive intermediates were independently generated in a site-specific manner in bottom-up-synthesized NCPs. Mechanistic studies employing a combination of chemical tools and site-specific mutagenesis revealed that histone proteins participate in DNA damage and repair processes in diverse ways.…”

Section: Introductionmentioning

confidence: 99%

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Participation of Histones in DNA Damage and Repair within Nucleosome Core Particles: Mechanism and Applications

2022

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Conspectus DNA is damaged by various endogenous and exogenous sources, leading to a diverse group of reactive intermediates that yield a complex mixture of products. The initially formed products are often metastable and can react to yield lesions that are more biologically deleterious. Mechanistic studies are frequently carried out on free DNA as the substrate. The observations do not necessarily reflect the reaction environment inside human cells where genomic DNA is condensed as chromatin in the nucleus. Chromatin is made up of monomeric structural units called nucleosomes, which are comprised of DNA wrapped around an octameric core of histone proteins (two copies each of histones H2A, H2B, H3, and H4). This account presents a summary of our work in the past decade on the mechanistic studies of DNA damage and repair in reconstituted nucleosome core particles (NCPs). A series of metastable lesions and reactive intermediates, such as abasic sites (AP), N7-methyl-2′-deoxyguanosine (MdG), and 2′-deoxyadenosin-N6-yl radical (dA•), have been independently generated in a site-specific manner in bottom-up-synthesized NCPs. Detailed mechanistic studies on these NCPs revealed that histones actively participate in DNA damage and repair processes in diverse ways. For instance, nucleophilic residues in the flexible histone N-terminal tails, such as Lys and N-terminal α-amine, react with electrophilic DNA damage and reactive intermediates. In some cases, transient intermediates are produced, leading to the promotion or suppression of damage and repair processes. In other examples, reactions with histones yield reversible or stable DNA–protein cross-links (DPCs). Histones also utilize acidic and basic residues, such as histidine and aspartic acid, to catalyze DNA strand cleavage through general acid/base catalysis. Alternatively, a Tyr in histone plays a vital role in nucleosomal DNA damage and repair via radical transfer. Finally, the reactivity discovered during the mechanistic studies has facilitated the development of new reagents and methods with applications in biotechnology. This research has enriched our knowledge of the roles of histone proteins in DNA damage and repair and their contributions to epigenetics and may have significant biological implications. The residues in histone N-terminal tails that react with DNA lesions also play pivotal roles in regulating the structure and function of chromatin, indicating that there may be cross-talk between DNA damage and repair in eukaryotic cells and epigenetic regulation. Also, in view of the biased amino acid composition of histones, these results provide hints about how the proteins have evolved to minimize their deleterious effects but maximize beneficial ones for maintaining genome integrity. Finally, previously unreported DPCs and histone post-translational modifications have been discovered through this research. The effects of these newly identified lesions on the structure and function of chromatin and their fates inside cells remain to be elucidated.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Participation of Histones in DNA Damage and Repair within Nucleosome Core Particles: Mechanism and Applications

2022

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“…They act to close the nucleosomes, inhibiting the expression of tumor suppressor genes. HDAC inhibitor, as an agonist of HDAC, can alter the abnormal hypoacetylation level of histone, and subsequently elicits cell differentiation and apoptosis, demonstrating the indispensable roles of HDACs in tumorigenesis (88)(89)(90)(91). Harnessing the function of HDACs is the premise indicating to precisely target the master alterations.…”

Section: Hdacs Classification and Functionsmentioning

confidence: 99%

Roles of Histone Deacetylases in Acute Myeloid Leukemia With Fusion Proteins

Zhang

Gao

2021

Front. Oncol.

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Accurate orchestration of gene expression is critical for the process of normal hematopoiesis, and dysregulation is closely associated with leukemogenesis. Epigenetic aberration is one of the major causes contributing to acute myeloid leukemia (AML), where chromosomal rearrangements are frequently found. Increasing evidences have shown the pivotal roles of histone deacetylases (HDACs) in chromatin remodeling, which are involved in stemness maintenance, cell fate determination, proliferation and differentiation, via mastering the transcriptional switch of key genes. In abnormal, these functions can be bloomed to elicit carcinogenesis. Presently, HDAC family members are appealing targets for drug exploration, many of which have been deployed to the AML treatment. As the majority of AML events are associated with chromosomal translocation resulting in oncogenic fusion proteins, it is valuable to comprehensively understand the mutual interactions between HDACs and oncogenic proteins. Therefore, we reviewed the process of leukemogenesis and roles of HDAC members acting in this progress, providing an insight for the target anchoring, investigation of hyperacetylated-agents, and how the current knowledge could be applied in AML treatment.

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“…[7] It is formed by wrapping a histone octamer with approximately 145 bp of DNA strand. [8,9] The nucleosome itself and its assemblies are known to play important roles in the regulation of gene expression [10,11] and formation of chromatin structures. [12] Research on dynamic behaviors of nucleosomes is indispensable to understanding the mechanisms of biological processes related to genomic DNA.…”

Section: Introductionmentioning

confidence: 99%

Evaluation by Experimentation and Simulation of a FRET Pair Comprising Fluorescent Nucleobase Analogs in Nucleosomes

Hirashima

Park

Sugiyama

2023

Chemistry A European J

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Förster resonance energy transfer (FRET) is an attractive tool for understanding biomolecular dynamics. FRET‐based analysis of nucleosomes has the potential to fill the knowledge gaps between static structures and dynamic cellular behaviors. Compared with typical FRET pairs using bulky fluorophores introduced by flexible linkers, fluorescent nucleoside‐based FRET pair has great potential since it can be fitted within the helical structures of nucleic acids. Herein we report on the construction of nucleosomes containing a nucleobase FRET pair and the investigation of experimental and theoretical FRET efficiencies through steady‐state fluorescence spectroscopy and calculation based on molecular dynamics simulations, respectively. Distinguishable experimental FRET efficiencies were observed depending on the positions of FRET pairs in nucleosomal DNA. The tendency could be supported by theoretical study. This work suggests the possibility of our approach to analyze structural changes of nucleosomes by epigenetic modifications or internucleosomal interactions.

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Nucleosomes and Epigenetics from a Chemical Perspective

Cited by 9 publications

References 148 publications

Participation of Histones in DNA Damage and Repair within Nucleosome Core Particles: Mechanism and Applications

Participation of Histones in DNA Damage and Repair within Nucleosome Core Particles: Mechanism and Applications

Roles of Histone Deacetylases in Acute Myeloid Leukemia With Fusion Proteins

Evaluation by Experimentation and Simulation of a FRET Pair Comprising Fluorescent Nucleobase Analogs in Nucleosomes

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