Pt-ttpy, a G-quadruplex binding platinum complex, induces telomere dysfunction and G-rich regions DNA damage
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA719668 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14141117.fastq.gz | Fastqsanger.gz | |||
| SRR14141118.fastq.gz | Fastqsanger.gz | |||
| SRR14141119.fastq.gz | Fastqsanger.gz | |||
| SRR14141120.fastq.gz | Fastqsanger.gz | |||
| SRR14141121.fastq.gz | Fastqsanger.gz |
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Project description:Pt-ttpy (tolyl terpyridin-Pt complex) covalently binds to G-quadruplex (G4) structures in vitro and to telomeres in cellulo via its Pt moiety. Here, we identified its targets in the human genome, in comparison to Pt-tpy, its derivative without G4 affinity, and cisplatin. Pt-ttpy, but not Pt-tpy, induces the release of the shelterin protein TRF2 from telomeres concomitantly to the formation of DNA damage foci at telomeres but also at other chromosomal locations. -H2AX chromatin immunoprecipitation (ChIP-seq) after treatment with Pt-ttpy or cisplatin revealed accumulation in G- and A-rich tandemly repeated sequences, but not particularly in potential G4 forming sequences. Collectively, Pt-ttpy presents dual targeting efficiency on DNA, by inducing telomere dysfunction and genomic DNA damage at specific loci.
2021-05-04 | GSE171450 | GEO
Project description:G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored. Here, we demonstrated that the G4-binding platinum(II) complex, Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study by RNA-seq, Chip- seq and CUT-RUN shows Pt-ttpy impairs most nuclear-encoded mt ribosome genes’ transcription initiation through dampening the recruiting of TAF1 and NELFB to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy's efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin. This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy.
2024-06-01 | GSE249026 | GEO
Project description:Platinum-based drugs (Pt drugs) are widely used in cancer chemotherapy, yet their genome-wide DNA binding patterns remain incompletely understood. Here, we present Pt-seq, an antibody-assisted, genome-wide method for mapping Pt-DNA adducts at single-base resolution. By employing exo- and endo- nucleases to remove background DNA, Pt-seq enables highly robust and sensitive profiling of binding sites for cisplatin, oxaliplatin, lobaplatin, and a Pt(IV) complex. Using Pt-seq, we identified hundreds to a few thousand binding clusters that are 10-20 kb in length and highly consistent among different Pt drugs. Notably, these binding clusters predominantly localize to centromeric and rDNA regions. In cisplatin-resistant cells, we found significantly reduced binding within these regions, suggesting a potential role in drug resistance. Moreover, we found that de novo mutations in cancer cells can create novel binding sites for Pt drugs. Based on this, we demonstrated that ICR-191, an acridine orange compound capable of inducing G insertions, enhances cisplatin-DNA crosslinking and sensitizes cells to Pt drugs. Collectively, Pt-seq sensitively profiles Pt drug-DNA interactions and deepens our understanding of the genome-wide effect of chemotherapeutic drugs.
2025-02-13 | GSE289501 | GEO
Project description:Pt-seq unveils the genomic binding pattern of platinum-based drugs [Pt-seq]
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Project description:Platinum-based drugs (Pt drugs) are widely used in cancer chemotherapy, yet their genome-wide DNA binding patterns remain incompletely understood. Here, we present Pt-seq, an antibody-assisted, genome-wide method for mapping Pt-DNA adducts at single-base resolution. By employing exo- and endo- nucleases to remove background DNA, Pt-seq enables highly robust and sensitive profiling of binding sites for cisplatin, oxaliplatin, lobaplatin, and a Pt(IV) complex. Using Pt-seq, we identified hundreds to a few thousand binding clusters that are 10-20 kb in length and highly consistent among different Pt drugs. Notably, these binding clusters predominantly localize to centromeric and rDNA regions. In cisplatin-resistant cells, we found significantly reduced binding within these regions, suggesting a potential role in drug resistance. Moreover, we found that de novo mutations in cancer cells can create novel binding sites for Pt drugs. Based on this, we demonstrated that ICR-191, an acridine orange compound capable of inducing G insertions, enhances cisplatin-DNA crosslinking and sensitizes cells to Pt drugs. Collectively, Pt-seq sensitively profiles Pt drug-DNA interactions and deepens our understanding of the genome-wide effect of chemotherapeutic drugs.
2025-02-13 | GSE289502 | GEO
Project description:The RNA-seq results reveal Tetra-Pt(bpy) has no effect on gene expression.
2015-10-15 | GSE74029 | GEO
Project description:Platinum drugs (Pt drugs) are one of the most widely used chemotherapy drugs in cancer treatment. Although the cytotoxic and resistant mechanisms of Pt drugs have been thoroughly explored, it remains elusive what factors affect the receptiveness of DNA to Pt drug-induced damage. A large fraction of the genome shows significantly altered Pt drug-induced DNA damage susceptibility in the in vivo nuclear environment in comparison to isolated DNA, which cannot be explained only by the transcriptional status and DNA accessibility of the chromatin regions in vivo. Here, we demonstrate that, besides local chromatin structure, the global nuclear locations of genomic regions play a key role in modulating Pt drug-induced DNA damage susceptibility in vivo. By integrating data from damage-seq experiments with 3D genome structure information we show that the preferential nuclear locations of genomic regions relative to specific nuclear bodies and nuclear compartments can explain patterns of Pt drug DNA damage susceptibility. Thus, our observations are consistent with recent in vitro observations of an enrichment of Pt drugs in biomolecular condensates linked to certain nuclear bodies. Finally, when mapping observed DNA damage-seq signals onto 3D genome structures, we found that the 3D nuclear distribution of Pt-drug induced DNA damage differs in drug resistant cells in comparison to drug sensitve cells. In particular DNA damage increases in gene poor chromatin preferentially located in the lamina compartment, while DNA damage is decreased in gene rich regions preferentially located at nuclear speckles. This change may deter Pt-drug induced DNA damage from more viable gene dense chromatin regions that are crucial for short term cell survival. This observation suggests a selective spatial redistribution of Pt drug action in the nucleus during the emergence of chemoresistance. These observations are relevant for a better understanding of Pt drug action and the development of cancer resistant cells.
2025-05-14 | GSE267578 | GEO
Project description:Platinum and palladium are highly sought-after noble metals that due to their low abundance have high value and because of their stability and their roles in catalytic processes are very desirable for industrial purposes. Bacteria are able to produce nanoparticles of platinum and palladium at low temperatures and from low concentration feedstocks contrary to chemical methods and so pose a potentially untapped ‘green’ resource for nanoparticle synthesis. We have used the bacterium Desulfovibrio alaskensis G20 to reduce Pt and Pd ions to zero-valent nanoparticle forms and used differential shotgun proteomics to identify proteins responsible for this reduction . There was found to be a core set of 13 proteins common to both datasets as well as 7 proteins specific to Pt and Pd individually. Over expression of one of Pt-specific genes; the NiFe hydrogenase small subunit, resulted in the formation of larger nanoparticles. For the first time the proteins involved in the metal reduction pathway have been pinpointed and it is our hope that these target genes can then be used for nanoparticle production to tailor specific properties for industrial purposes at the genetic level rather than post-production.
2021-08-30 | PXD004457 | Pride
Project description:Platinum (II) complexes such as cisplatin among the few others are well-known and approved for clinical use as anticancer metal-based drugs. In spite of their successful and wide acceptance, the respective chemotherapy is associated with severe side effects and the ability of tumors to quickly develop resistance. To overcome these drawbacks the novel strategy is considered, which is based on the use of platinum complexes with bioactive ligands attached to act in synergy with platinum and further improve its pharmacological properties. Among the recently introduced such multi-action prodrugs is Pt(IV) complex with two lonidamine ligands, the latter selectively inhibiting hexokinase and, thus, the glycolysis in cancer cells. While platinum based multi-action prodrugs are exhibiting increased levels of activity towards cancer cells and, thus, considered as potent to overcome the resistance to cisplatin, there is a crucial need to uncover their mechanism of action by revealing all possibly affected processes and targets across the whole cellular proteomes. These are the challenging tasks in proteomics requiring high-throughput analysis of hundreds of samples for just a single drug-to-proteome system. In this work we performed these analyses for 8-azaguanine and experimental Pt(IV)-lonidamine complex applied to ovarian cancer cell line A2780, using both mechanism- and compound-centric chemical proteomics approaches based on ultrafast expression proteomics and thermal proteome profiling, respectively. Analysis of data obtained for Pt(IV)-lonidamine complex revealed regulation of proteins involved in glucose metabolic process associated with lonidamine further supporting the multi-action mechanism of this prodrug action.
2025-05-26 | PXD058413 | Pride