Dataset Information

Degradation of G-Quadruplex Binding Proteins in Chromatin Using G4-Ligand-Based PROTACs

ABSTRACT: Targeted protein degradation can intervene with the function of disease-related proteins, but most current approaches rely on direct ligand engagement of a protein target, limiting their applicability to proteins that are difficult to bind selectively. We present a conceptually unique approach to degrade proteins associated with DNA G-quadruplex (G4) secondary structures in a chromatin context. G4s are non-canonical nucleic acid structures that form at regulatory regions of transcriptionally active genes in open chromatin, and are abundant in cancer states. While many proteins recognize or regulate G4 structures, selectively targeting G4-binding proteins in their native chromatin environment is challenging. Our bifunctional molecules are PROTACs that bind naturally occurring G4s, recruit E3 ubiquitin ligases and degrade G4-specific transcription factors and chromatin remodelers such as FUS, SMARCA4, and ATRX. These proteins are important therapeutic targets that play crucial roles in transcription regulation and DNA repair. Our approach has the potential to be exploited in a therapeutic strategy to target diseases characterized by aberrant G4 activity, such as cancers.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Samuel Lord

LAB HEAD: Shankar Balasubramanian

PROVIDER: PXD073248 | Pride | 2026-01-27

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	03062024_Ascend_PR1795_FP_.msf	Msf
	03062024_Ascend_PR1795_FP_01.raw	Raw
	03062024_Ascend_PR1795_FP_02.raw	Raw
	03062024_Ascend_PR1795_FP_03.raw	Raw
	03062024_Ascend_PR1795_FP_04.raw	Raw

Items per page:

1 - 5 of 47

Similar Datasets

Project description:DNA secondary structures are important for fundamental genome functions such as transcription and replication1. The G-quadruplex (G4) structural motif has been linked to gene regulation2,3 and genome instability4,5 and may be important to cancer development and other diseases6-8. Recently, ~700,000 discrete G4s have been observed in naked human single-stranded genomic DNA using G4-seq, a high-throughput sequencing technique that detects structural features in vitro.9 It is of vital importance to investigate G4 structures within an endogenous chromatin context, which until now remained elusive10,11. Herein, we address this via the development of G4 ChIP-seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We identified ~10,000 endogenous G4 structures and show that G4s are predominantly seen in regulatory, nucleosome-depleted, chromatin regions. G4s were enriched in the promoters and 5âUTR regions of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as MYC. Reorganization of the chromatin landscape using a histone deacetylase inhibitor, resulted in de novo G4 formation in new and more prominent regulatory, nucleosome-depleted regions associated with increased transcriptional output. Our findings suggest a striking relationship between promoter nucleosome-depleted regions, G4 formation and elevated transcriptional activity. Comparison between normal human epidermal keratinocytes and their immortalized counterparts revealed a ï¾7-fold greater G4 abundance in immortalized cells, of which 80 % were found in regulatory, nucleosome-depleted regions common to both cell types. Consequently, cells exhibiting more G4s displayed significantly increased transcriptional output and were more sensitive to growth inhibition by a small molecule G4 ligand. Overall, our results provide new mechanistic insights into where and when DNA adopts G4 structure in vivo. Our findings show for the first time that regulatory, nucleosome-depleted chromatin and transcriptional states predominantly shape the endogenous G4 DNA landscape. Two cell lines, treated with entinostat or untreated, analyzed to detect gene expression differences, presence of G-Qudruplexes and chromatin state. Each combination of conditions replicated in duplicates or triplicates.

Dataset Information

Degradation of G-Quadruplex Binding Proteins in Chromatin Using G4-Ligand-Based PROTACs

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets