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Chandramouly G , McDevitt S , Sullivan K , Kent T , Luz A , Glickman JF , Andrake M , Skorski T , Pomerantz RT
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
PMID: 26548611    PMCID: PMC4701204    URL: https://www.ncbi.nlm.nih.gov/pubmed/26548611
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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.
Chandramouly, Gurushankar McDevitt, Shane Sullivan, Katherine Kent, Tatiana Luz, Antonio Glickman, J Fraser Andrake, Mark Skorski, Tomasz Pomerantz, Richard T eng R01 CA186238/CA/NCI NIH HHS/ R01 CA190237/CA/NCI NIH HHS/ 1R01CA186238/CA/NCI NIH HHS/ 1R01CA190237-01/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Chem Biol. 2015 Nov 19;22(11):1491-1504. doi: 10.1016/j.chembiol.2015.10.003. Epub 2015 Nov 5.