Analysis of the Activities of RAD54, a SWI2/SNF2 Protein, Using a Specific Small-molecule Inhibitor

Deakyne, Julianna S.; Huang, Fei; Negri, Joseph; Tolliday, Nicola; Simon, Chantal; Mazin, Alexander V.

doi:10.1074/jbc.m113.502195

Cited by 18 publications

(19 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A pilot HTS screen of the Broad Institute validation library (3000 compounds) using a FRET-based assay for branch migration of Holliday junctions by RAD54 yielded several promising RAD54 inhibitors (Deakyne et al, 2013). The assay showed high robustness and consistency (Z’ of 0.825 – 0.875) and will be valuable for identification of inhibitors of other branch-migrating enzymes.…”

Section: Parp1 and Recq1 Dna Helicasementioning

confidence: 99%

Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy

Hengel

Spies

2017

Cell Chemical Biology

118

126

View full text Add to dashboard Cite

To maintain stable genomes and to avoid cancer and aging, cells need to repair a multitude of deleterious DNA lesions, which arise constantly in every cell. Processes that support genome integrity in normal cells, however, allow cancer cells to develop resistance to radiation and DNA damaging chemotherapeutics. Chemical inhibition of the key DNA repair proteins and pharmacologically induced synthetic lethality have become instrumental in both dissecting the complex DNA repair networks and as promising anticancer agents. The difficulty in capitalizing on synthetically lethal interactions in cancer cells is that many potential targets do not possess well-defined small molecule binding determinates. In this review we will discuss several successful campaigns to identify and leverage small-molecule inhibitors of the DNA repair proteins, from PARP1, a paradigm case for clinically successful small molecule inhibitors, to coveted new targets, such as RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease and WRN DNA helicase.

show abstract

Section: Parp1 and Recq1 Dna Helicasementioning

confidence: 99%

Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy

Hengel

Spies

2017

Cell Chemical Biology

118

126

View full text Add to dashboard Cite

show abstract

“…For instance, metatungstate and RS-1 that lock RAD51 in an inactive and active state 23, 27 , respectively, likely reveal physiologically relevant mechanisms of RAD51 regulation. Experiments with SN provided important insight to the role of RAD54 ATPase 42 . The study with metatungstate showed the importance of structural approaches for the analysis of biochemical activities using small molecule inhibitors 27 .…”

Section: Discussionmentioning

confidence: 99%

“…3) 42, 43 . A fluorophore and a quencher group were attached to DNA substrates opposing each other so that dissociation of these substrates due to RAD54 branch migration or BLM DNA unwinding (helicase) activities resulted in an increase of the fluorescence intensity.…”

Section: Inhibitors Of Helicases and Helicase-like Proteins Involved mentioning

confidence: 99%

“…Streptonigrin (SN) ( 8 ) (Table 1), an aminoquinone compound 45 , was identified as an inhibitor of the RAD54 branch migration activity by screening a 2000-compound library using fluorescence-quenching assay with synthetic Holliday junction substrates (Fig. 3) 42 . The IC 50 of RAD54 (0.1 μM) inhibition by SN is16.5 μM; inhibition was specific as SN does not affect the branch migration activity of EcRuvAB or DNA strand exchange activity of human RAD51.…”

Section: Inhibitors Of Helicases and Helicase-like Proteins Involved mentioning

confidence: 99%

See 1 more Smart Citation

Targeting the homologous recombination pathway by small molecule modulators

Huang

Mazin

2014

Bioorganic & Medicinal Chemistry Letters

Self Cite

View full text Add to dashboard Cite

During the last decade, the use of small molecule (MW< 500 Dalton) compounds that modulate (inhibit or activate) important proteins of different biological pathways became widespread. Recently, the homologous recombination (HR) pathway emerged as a target for such modulators. Development of small molecule modulators pursues two distinct but not mutually exclusive purposes: to create a research tool to study the activities or functions of proteins of interest and to produce drugs targeting specific pathologies. Here, we review the progress of small molecule development in the area of HR.

show abstract

“…Furthermore, nucleosome repositioning activity is underpinned by DNA translocation in most models (85,(91)(92)(93)(94)(95). Qualitative demonstrations of DNA translocation by chromatin remodelers, have recently been extended by quantitative determinations of the kinetic mechanism of translocation (87,88,96,97).…”

Section: Dna Translocation By Chromatin Remodeling Enzymesmentioning

confidence: 99%

All motors have to decide is what to do with the DNA that is given them

Briggs

Fischer

2014

Biomolecular Concepts

View full text Add to dashboard Cite

DNA translocases are a diverse group of molecular motors responsible for a wide variety of cellular functions. The goal of this review is to identify common aspects in the mechanisms for how these enzymes couple the binding and hydrolysis of ATP to their movement along DNA. Not surprisingly, the shared structural components contained within the catalytic domains of several of these motors appear to give rise to common aspects of DNA translocation. Perhaps more interesting, however, are the differences between the families of translocases and the potential associated implications both for the functions of the members of these families and for the evolution of these families. However, as there are few translocases for which complete characterizations of the mechanisms of DNA binding, DNA translocation, and DNA-stimulated ATPase have been completed, it is difficult to form many inferences. We therefore hope that this review motivates the necessary further experimentation required for broader comparisons and conclusions.

show abstract

Analysis of the Activities of RAD54, a SWI2/SNF2 Protein, Using a Specific Small-molecule Inhibitor

Cited by 18 publications

References 66 publications

Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy

Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy

Targeting the homologous recombination pathway by small molecule modulators

All motors have to decide is what to do with the DNA that is given them

Contact Info

Product

Resources

About