Inhibition of transcription by platinum antitumor compounds

Ryan C Todd1, Stephen J Lippard

  • 1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Insights

Platinum anticancer drugs like cisplatin induce apoptosis by damaging DNA, inhibiting transcription. Understanding these platinum-DNA adducts

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Pharmacology

Background:

  • Cisplatin, carboplatin, and oxaliplatin are FDA-approved platinum-based anticancer drugs.
  • These drugs function by binding to nuclear DNA, forming adducts.
  • These platinum-DNA adducts trigger cellular responses, including transcription inhibition.

Purpose of the Study:

  • To review structural investigations of platinum-DNA adducts and their effects on DNA geometry.
  • To detail research on transcription inhibition by platinum-DNA adducts.
  • To mechanistically analyze how DNA structural distortions from platinum damage inhibit RNA synthesis.

Main Methods:

  • Review of structural investigations of platinum-DNA adducts.
  • Analysis of research on transcription inhibition by platinum-DNA adducts.
  • Mechanistic analysis of DNA damage-induced RNA synthesis inhibition.

Main Results:

  • Detailed review of Pt-DNA adduct structures and their impact on global DNA geometry.
  • Research findings demonstrating transcription inhibition by Pt-DNA adducts.
  • Mechanistic insights into how DNA distortions caused by platinum drugs impede RNA synthesis.

Conclusions:

  • Understanding the molecular mechanisms of platinum-based anticancer agents is crucial.
  • Elucidating the effects of Pt-DNA adducts on DNA structure and transcription is key.
  • This knowledge will aid in the development of novel platinum-based anticancer drugs.

Related Concept Videos

Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...
Inhibitors of Bacterial Protein Synthesis01:25

Inhibitors of Bacterial Protein Synthesis

Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
Inhibitors of Bacterial DNA Synthesis01:28

Inhibitors of Bacterial DNA Synthesis

Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These antibiotics are selectively...
Transcription Attenuation in Prokaryotes02:42

Transcription Attenuation in Prokaryotes

Transcriptional attenuation occurs when RNA transcription is prematurely terminated due to the formation of a terminator mRNA hairpin structure.  Bacteria use these hairpins to regulate the transcription process and control the synthesis of several amino acids including histidine, lysine, threonine, and phenylalanine. Transcription attenuation takes place in the non-coding regions of mRNA.
There are several different mechanisms used to attenuate transcription. In ribosome mediated...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...