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DNA damage induced by G-quadruplex ligand PyBI and its synthetic lethality with DNA repair inhibitors in cancer cells

ABSTRACT: The existence of G-quadruplexes (G4s) in vivo verified by diverse techniques, accompanied with their regulatory roles in cellular processes, highlight G4s as a target for various disease treatment. Targeting G-quadruplex DNAs to cause DNA damage has a good prospect for cancer therapy. However, previous studies on DNA damage induced by G4 ligands and its repair response thereof mainly focused on limited scaffolds such as CX series drugs, PDS families, etc. Here, we systematically investigated the DNA damage and repair mechanism induced by a good G4 stabilizer with bis(benzimidazole)pyridine as its key scaffold, which we termed as PyBI. PyBI can stabilize G4s both in vitro and in vivo, and cause DNA double strand breaks (DSB) and genome instability during DNA replication, resulting in cell cycle stagnation in G2/M phase and the increase of RAD51 and 53BP1 foci. Significantly, we applied Cleavage Under Targets and Tagmentation (CUT&Tag) for genome-wide mapping DNA damage sites induced by PyBI in cancer cells. Together with its G4 mapping result by CUT&Tag, we revealed that DNA damage caused by PyBI might be mediated by G4 stabilization. Moreover, we thoroughly investigated the synthetic lethality of PyBI with a small library of DNA repair inhibitors. PyBI exhibited good synthetic lethality effects with RAD51 and DNA-PK inhibitor, providing a new prospect for the treatment of genetically defective cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270287 | GEO | 2025/05/29

REPOSITORIES: GEO

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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.

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DNA damage induced by G-quadruplex ligand PyBI and its synthetic lethality with DNA repair inhibitors in cancer cells

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