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.
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DOI：
10.1016/j.chembiol.2015.10.003
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发表时间：
2015-11-19
影响因子：
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通讯作者：
Pomerantz RT
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文献类型：
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作者：
Chandramouly G;McDevitt S;Sullivan K;Kent T;Luz A;Glickman JF;Andrake M;Skorski T;Pomerantz RT
RAD 52的抑制导致BRCA缺陷细胞的合成致死性。然而，结合单链DNA（ssDNA）且缺乏酶活性的RAD 52的药理学抑制尚未得到证实。在这里，我们确定小分子6-羟基-多巴（6-OH-多巴）作为一个主要的变构抑制剂的RAD 52 ssDNA结合域。例如，我们发现多个小分子结合并完全将RAD 52十一聚体环转化为二聚体，这消除了晶体结构中观察到的ssDNA结合通道。6-OH-多巴还破坏了RAD 52七聚体和十一聚体环的超结构，并抑制了细胞中RAD 52的募集和重组活性，对其他双链断裂修复途径的影响可以忽略不计。重要的是，我们发现6-OH-多巴选择性地抑制BRCA缺陷癌细胞的增殖，包括那些从白血病患者中获得的细胞。综上所述，这些数据表明，RAD 52环的小分子破坏是BRCA缺陷型癌症中精确医学的一种有前途的机制。
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-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.