2. Academic Validation
  3. Small-Molecule Disruption of RAD52 Rings as a Mechanism for Precision Medicine in BRCA-Deficient Cancers

Small-Molecule Disruption of RAD52 Rings as a Mechanism for Precision Medicine in BRCA-Deficient Cancers

  • Chem Biol. 2015 Nov 19;22(11):1491-1504. doi: 10.1016/j.chembiol.2015.10.003.
Gurushankar Chandramouly 1,  Shane McDevitt 1,  Katherine Sullivan 2,  Tatiana Kent 1,  Antonio Luz 3,  J Fraser Glickman 3,  Mark Andrake 4,  Tomasz Skorski 2,  Richard T Pomerantz 5
Affiliations

Affiliations

  • 1 Department of Medical Genetics and Molecular Biochemistry, Fels Institute for Cancer Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
  • 2 Department of Microbiology and Immunology, Fels Institute for Cancer Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
  • 3 High-Throughput and Spectroscopy Resource Center, The Rockefeller University, New York, NY 10065, USA.
  • 4 Institute for Cancer Research, Fox Chase Cancer Center, Temple Health, Philadelphia, PA 19111, USA.
  • 5 Department of Medical Genetics and Molecular Biochemistry, Fels Institute for Cancer Research, Temple University School of Medicine, Philadelphia, PA 19140, USA. Electronic address: [email protected].
PMID: 26548611 DOI: 10.1016/j.chembiol.2015.10.003
Abstract

Suppression of RAD52 causes synthetic lethality in BRCA-deficient cells. Yet pharmacological inhibition of RAD52, which binds single-strand DNA (ssDNA) and lacks enzymatic activity, has not been demonstrated. Here, we identify the small molecule 6-hydroxy-DL-dopa (6-OH-dopa) as a major allosteric inhibitor of the RAD52 ssDNA binding domain. For example, we find that multiple small molecules bind to and completely transform RAD52 undecamer rings into dimers, which abolishes the ssDNA binding channel observed in crystal structures. 6-OH-Dopa also disrupts RAD52 heptamer and undecamer ring superstructures, and suppresses RAD52 recruitment and recombination activity in cells with negligible effects on other double-strand break repair pathways. Importantly, we show that 6-OH-dopa selectively inhibits the proliferation of BRCA-deficient Cancer cells, including those obtained from leukemia patients. Taken together, these data demonstrate small-molecule disruption of RAD52 rings as a promising mechanism for precision medicine in BRCA-deficient cancers.

Keywords

DNA repair; cancer; cancer therapeutics; genome instability; high-throughput screening; homologous recombination; single-strand annealing; synthetic lethality.

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