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DNA topoisomerases and their poisoning by anticancer and antibacterial drugs.
Rif1 provides a new DNA‐binding interface for the Bloom syndrome complex to maintain normal replication
V vertebrate Rif1 contains a DNA‐binding domain that resembles the αCTD domain of bacterial RNA polymerase α; and this domain preferentially binds fork and Holliday junction (HJ) DNA in vitro and is required for R if1 to resist replication stress in vivo.
Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents
- G. Zoppoli, M. Regairaz, Y. Pommier
- BiologyProceedings of the National Academy of Sciences
- 27 August 2012
It is concluded that SLFN11 expression is causally associated with the activity ofDDAs in cancer cells, has a broad expression range in colon and ovarian adenocarcinomas, and may behave as a biomarker for prediction of response to DDAs in the clinical setting.
The SMARCA2/4 ATPase Domain Surpasses the Bromodomain as a Drug Target in SWI/SNF-Mutant Cancers: Insights from cDNA Rescue and PFI-3 Inhibitor Studies.
Together, these complementary genetic and pharmacologic studies exemplify a general strategy for multidomain protein drug-target validation and in case of SMARCA2/4 highlight the potential for drugging the more challenging helicase/ATPase domain to deliver on the promise of synthetic-lethality therapy.
Inhibition of histone deacetylase in cancer cells slows down replication forks, activates dormant origins, and induces DNA damage.
It is found that pharmacologic concentrations of SAHA induce replication-mediated DNA damage with activation of histone gammaH2AX, establishing a critical link between robust chromatin acetylation and DNA replication in human cancer cells.
Hexameric ring structure of human MCM10 DNA replication factor
The molecular structure of human MCM10 is a ring‐shaped hexamer with large central and smaller lateral channels and a system of inner chambers that suggests that this important protein uses its architecture to provide a docking module for assembly of the molecular machinery required for eukaryotic DNA replication.
SLFN11 Blocks Stressed Replication Forks Independently of ATR.
Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2.
Structural studies on apo-, peptide-and small molecule-ATAD2 complexes revealed that the bromodomain adopts a 'closed', histone-compatible conformation and a more 'open' ligand- compatible conformation of the binding site respectively.
Human SIRT1 regulates DNA binding and stability of the Mcm10 DNA replication factor via deacetylation
- Samuel T. Fatoba, Silvia Tognetti, A. L. Okorokov
- Biology, ChemistryNucleic acids research
- 28 February 2013
This study highlights the importance of protein acetylation for DNA replication initiation and progression, and suggests that SIRT1 may mediate a crosstalk between cellular circuits controlling metabolism and DNA synthesis.
Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor.
- W. Palmer, G. Poncet-Montange, J. Andersen
- Biology, ChemistryJournal of medicinal chemistry
- 25 February 2016
A unique binding mode enabled the design of a potent and selective inhibitor 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 with high cellular potency and favorable pharmacokinetic properties for in vitro and in vivo evaluation.