Transcription-facilitating histone chaperons interact with genomic and synthetic G4 structures

Pavlova, Iulia; Цветков, В. Б.; Isaakova, Ekaterina; Severov, V. V.; Khomyakova, E. A.; Lacis, Ivan A.; Лазарев, В. Н.; Lagarkova, Maria A.; Pozmogova, Galina E.; Varizhuk, Anna M.

doi:10.1016/j.ijbiomac.2020.05.173

Cited by 8 publications

(4 citation statements)

References 75 publications

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“…For G4 docking to CTCF, we used the available model of CTCF zinc fingers 4-10 [10] in complex with a DNA duplex (PDB ID: 5UND) and removed the duplex. The MYC-G4 model, referred to as 'Pu27 truncated' in a previous work (29) was obtained from the Pu24T model (PDB ID: 2N6C) as described previously [51]. A two-step docking procedure was carried out following a published protocol [52].…”

Section: Molecular Modelingmentioning

confidence: 99%

DNA G-Quadruplexes Contribute to CTCF Recruitment

Tikhonova

Pavlova

Isaakova

et al. 2021

IJMS

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G-quadruplex (G4) sites in the human genome frequently colocalize with CCCTC-binding factor (CTCF)-bound sites in CpG islands (CGIs). We aimed to clarify the role of G4s in CTCF positioning. Molecular modeling data suggested direct interactions, so we performed in vitro binding assays with quadruplex-forming sequences from CGIs in the human genome. G4s bound CTCF with Kd values similar to that of the control duplex, while respective i-motifs exhibited no affinity for CTCF. Using ChIP-qPCR assays, we showed that G4-stabilizing ligands enhance CTCF occupancy at a G4-prone site in STAT3 gene. In view of the reportedly increased CTCF affinity for hypomethylated DNA, we next questioned whether G4s also facilitate CTCF recruitment to CGIs via protecting CpG sites from methylation. Bioinformatics analysis of previously published data argued against such a possibility. Finally, we questioned whether G4s facilitate CTCF recruitment by affecting chromatin structure. We showed that three architectural chromatin proteins of the high mobility group colocalize with G4s in the genome and recognize parallel-stranded or mixed-topology G4s in vitro. One of such proteins, HMGN3, contributes to the association between G4s and CTCF according to our bioinformatics analysis. These findings support both direct and indirect roles of G4s in CTCF recruitment.

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Section: Molecular Modelingmentioning

confidence: 99%

DNA G-Quadruplexes Contribute to CTCF Recruitment

Tikhonova

Pavlova

Isaakova

et al. 2021

IJMS

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“…The permissive role of the promoter/enhancer G4s in the gene expression can be attributed to the accumulation of TFs, including the LLPS drivers TAF15 [6], SP1 [78], and, possibly, BET proteins [79]. The direct binding to G4s in vitro was demonstrated for the BET protein BRD3 [34,79], which shares key structural features and functions with its homologues BRD4 and BRD2. These proteins recognize acetylated chromatin through their bromodomains (BD) and remodel nucleosomes to maintain Pol II processivity during the transcription elongation [126].…”

Section: G4s May Assist In Assembling Transcription Initiation-and Re...mentioning

confidence: 99%

G-Quadruplexes in Nuclear Biomolecular Condensates

Pavlova

Iudin

Surdina

et al. 2023

Genes

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G-quadruplexes (G4s) have long been implicated in the regulation of chromatin packaging and gene expression. These processes require or are accelerated by the separation of related proteins into liquid condensates on DNA/RNA matrices. While cytoplasmic G4s are acknowledged scaffolds of potentially pathogenic condensates, the possible contribution of G4s to phase transitions in the nucleus has only recently come to light. In this review, we summarize the growing evidence for the G4-dependent assembly of biomolecular condensates at telomeres and transcription initiation sites, as well as nucleoli, speckles, and paraspeckles. The limitations of the underlying assays and the remaining open questions are outlined. We also discuss the molecular basis for the apparent permissive role of G4s in the in vitro condensate assembly based on the interactome data. To highlight the prospects and risks of G4-targeting therapies with respect to the phase transitions, we also touch upon the reported effects of G4-stabilizing small molecules on nuclear biomolecular condensates.

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“…BRD3 contains a bromo-domain capable of binding acetylated histones, allowing for the recruitment of RNA polymerase and initiation of transcription ( 30 ). The idea that G4s interact with BRD3 within cells has been substantiated by BG4 ChIP-seq and BRD3 ChIP-seq analysis, which revealed a significant colocalization of G4 motifs within BRD3 occupancy sites ( 31 ). Additionally, the interaction between G4s and BRD3 does not prevent its binding to acetylated histones or other chromatin remodelers, suggesting that BRD3-G4 interactions might instead guide the recruitment of chromatin remodelling complexes to favour transcription at G4-sites (Figure 2C ).…”

Section: Introductionmentioning

confidence: 99%

“…However, various in vitro studies have demonstrated the high affinity of multiple regulatory proteins for G4 structures including, eukaryotic transcription factors SP1 ( 61 ), MAZ ( 62 ) and YY1 ( 63 ) and viral regulatory proteins such as the transcription factor ICP4 ( 64 ). Additionally, proteins that form part of large transcription-enhancing complexes such as the transcriptional co-activator BRD3 ( 29 , 31 ) and the chromatin regulating protein PARP-1 ( 65 ) have been shown to interact strongly with G4s. Within cells, enhancers and promoters containing G4-forming sequences additionally have significantly higher levels of transcription factor binding, which is accompanied by increased levels of RNA pol II occupancy and transcriptional activity ( 17 , 20 , 58 ).…”

Section: Introductionmentioning

confidence: 99%

DNA G-quadruplex structures: more than simple roadblocks to transcription?

Robinson

Raguseo

Nuccio

et al. 2021

Nucleic Acids Research

176

142

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It has been >20 years since the formation of G-quadruplex (G4) secondary structures in gene promoters was first linked to the regulation of gene expression. Since then, the development of small molecules to selectively target G4s and their cellular application have contributed to an improved understanding of how G4s regulate transcription. One model that arose from this work placed these non-canonical DNA structures as repressors of transcription by preventing polymerase processivity. Although a considerable number of studies have recently provided sufficient evidence to reconsider this simplistic model, there is still a misrepresentation of G4s as transcriptional roadblocks. In this review, we will challenge this model depicting G4s as simple ‘off switches’ for gene expression by articulating how their formation has the potential to alter gene expression at many different levels, acting as a key regulatory element perturbing the nature of epigenetic marks and chromatin architecture.

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Transcription-facilitating histone chaperons interact with genomic and synthetic G4 structures

Cited by 8 publications

References 75 publications

DNA G-Quadruplexes Contribute to CTCF Recruitment

DNA G-Quadruplexes Contribute to CTCF Recruitment

G-Quadruplexes in Nuclear Biomolecular Condensates

DNA G-quadruplex structures: more than simple roadblocks to transcription?

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