Disruption of nucleosomes by DNA groove binders of clinical significance and implications for chromatin remodeling

Lorch, Yahli; Maier-Davis, Barbara

doi:10.1073/pnas.2216611120

Cited by 4 publications

(3 citation statements)

References 28 publications

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“…Netropsin is one of the first discovered ligands that selectively binds to the minor groove of DNA and prevents HMGA1 from binding to DNA [ 42 , 43 ]. It was previously reported to have antiviral activity and was subsequently shown to have cytostatic activity against tumor cell lines [ 42 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

The RP11-417E7.1/THBS2 signaling pathway promotes colorectal cancer metastasis by activating the Wnt/β-catenin pathway and facilitating exosome-mediated M2 macrophage polarization

Liu,

Lv,

Liu

et al. 2024

J Exp Clin Cancer Res

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Background Metastasis is the major cause of colorectal cancer (CRC) mortality. Emerging evidence suggests that long noncoding RNAs (lncRNAs) drive cancer metastasis and that their regulatory pathways could be targeted for preventing metastasis. However, the underlying mechanisms of lncRNAs in CRC metastasis remain poorly understood. Methods Microarray analysis was used to screen for differentially expressed lncRNAs. Transwell assays, fibronectin cell adhesion assays, and mouse metastasis models were utilized to evaluate the metastatic capacities of CRC in vitro and in vivo. Chromatin isolation by RNA purification, chromatin immunoprecipitation and chromosome conformation capture were applied to investigate the underlying mechanism involved. qRT‒PCR and transmission electron microscopy were performed to confirm macrophage polarization and the presence of cancer-derived exosomes. Results The lncRNA RP11-417E7.1 was screened and identified as a novel metastasis-associated lncRNA that was correlated with a poor prognosis. RP11-417E7.1 enhances the metastatic capacity of CRC cells in vivo and in vitro. Mechanistically, RP11-417E7.1 binding with High mobility group A1 (HMGA1) promotes neighboring thrombospondin 2 (THBS2) transcription via chromatin loop formation between its promoter and enhancer, which activates the Wnt/β-catenin signaling pathway and facilitates CRC metastasis. Furthermore, exosomes derived from CRC cells transport THBS2 into macrophages, thereby inducing the M2 polarization of macrophages to sustain the prometastatic microenvironment. Notably, netropsin, a DNA-binding drug, suppresses chromatin loop formation mediated by RP11-417E7.1 at the THBS2 locus and significantly inhibits CRC metastasis in vitro and in vivo. Conclusions This study revealed the novel prometastatic function and mechanism of the lncRNA RP11-417E7.1, which provides a potential prognostic indicator and therapeutic target in CRC.

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Section: Discussionmentioning

confidence: 99%

The RP11-417E7.1/THBS2 signaling pathway promotes colorectal cancer metastasis by activating the Wnt/β-catenin pathway and facilitating exosome-mediated M2 macrophage polarization

Liu,

Lv,

Liu

et al. 2024

J Exp Clin Cancer Res

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“…Abundant positive charge of lysine and arginine residues in the tails drives chromatin remodeling. This role is general, applicable not only to remodeling by RSC but also to nucleosome disruption by other agents, such as small molecules that bind only to DNA and not to modified or unmodified tail residues ( 34 ). This role of the tails is fundamental, as the occurrence of lysine residues in the tails must have preceded their function as targets of posttranslational modification.…”

Section: Discussionmentioning

confidence: 99%

Role of the histone tails in histone octamer transfer

Lorch

Kornberg

Maier-Davis

2023

Nucleic Acids Research

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The exceptionally high positive charge of the histones, concentrated in the N- and C-terminal tails, is believed to contribute to the stability of the nucleosome by neutralizing the negative charge of the nucleosomal DNA. We find, on the contrary, that the high positive charge contributes to instability, performing an essential function in chromatin remodeling. We show that the tails are required for removal of the histone octamer by the RSC chromatin remodeling complex, and this function is not due to direct RSC–tail interaction. We also show that the tails are required for histone octamer transfer from nucleosomes to DNA, and this activity of the tails is a consequence of their positive charge. Thus, the histone tails, intrinsically disordered protein regions, perform a critical role in chromatin structure and transcription, unrelated to their well-known role in regulation through posttranscriptional modification.

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“…Minor groove-binding drugs have been primarily AT-specific agents such as netropsin, pentamidine, Hoechst dyes, DAPI, Ridinilazole, and many related compounds. Such compounds have a wide range of applications in biotechnology and therapeutics. − Drugs, including those from natural products, that target the major groove are also of interest and have many possible applications. , Unfortunately, it has proven much more difficult to selectively target the major groove, and the minor groove has been the target of most research to date. Also, targeting the minor groove of double-helical structures of RNA with selective compounds is of major interest; however, selective targeting of the RNA minor groove with small molecules can be challenging because of the shape of its helical dsRNA. − …”

Section: Introductionmentioning

confidence: 99%

X-ray Structure Characterization of the Selective Recognition of AT Base Pair Sequences

Ogbonna

Farahat

Terrell

et al. 2023

ACS Bio Med Chem Au

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The rational design of small molecules that target specific DNA sequences is a promising strategy to modulate gene expression. This report focuses on a diamidinobenzimidazole compound, whose selective binding to the minor groove of AT DNA sequences holds broad significance in the molecular recognition of AT-rich human promoter sequences. The objective of this study is to provide a more detailed and systematized understanding, at an atomic level, of the molecular recognition mechanism of different AT-specific sequences by a rationally designed minor groove binder. The specialized method of X-ray crystallography was utilized to investigate how the sequence-dependent recognition properties in general, A-tract, and alternating AT sequences affect the binding of diamidinobenzimidazole in the DNA minor groove. While general and A-tract AT sequences give a narrower minor groove, the alternating AT sequences intrinsically have a wider minor groove which typically constricts upon binding. A strong and direct hydrogen bond between the N-H of the benzimidazole and an H-bond acceptor atom in the minor groove is essential for DNA recognition in all sequences described. In addition, the diamidine compound specifically utilizes an interfacial water molecule for its DNA binding. DNA complexes of AATT and AAAAAA recognition sites show that the diamidine compound can bind in two possible orientations with a preference for water-assisted hydrogen bonding at either cationic end. The complex structures of AAATTT, ATAT, ATATAT, and AAAA are bound in a singular orientation. Analysis of the helical parameters shows a minor groove expansion of about 1 Å across all the nonalternating DNA complexes. The results from this systematic approach will convey a greater understanding of the specific recognition of a diverse array of AT-rich sequences by small molecules and more insight into the design of small molecules with enhanced specificity to AT and mixed DNA sequences.

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Disruption of nucleosomes by DNA groove binders of clinical significance and implications for chromatin remodeling

Cited by 4 publications

References 28 publications

The RP11-417E7.1/THBS2 signaling pathway promotes colorectal cancer metastasis by activating the Wnt/β-catenin pathway and facilitating exosome-mediated M2 macrophage polarization

The RP11-417E7.1/THBS2 signaling pathway promotes colorectal cancer metastasis by activating the Wnt/β-catenin pathway and facilitating exosome-mediated M2 macrophage polarization

Role of the histone tails in histone octamer transfer

X-ray Structure Characterization of the Selective Recognition of AT Base Pair Sequences

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