BRCA1 and HSP90 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation
BRCA1 and HSP90 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation
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DOI：
10.1073/pnas.1203326109
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发表时间：
2012-08-21
影响因子：
11.1
通讯作者：
Jensen, Roy A.
中科院分区：
文献类型：
--
作者：
Stecklein, Shane R.;Kumaraswamy, Easwari;Jensen, Roy A.
人类乳腺癌和卵巢癌中功能性乳腺癌易感基因 1 (BRCA1) 的表达与铂类化疗药物和聚 (ADP 核糖) 聚合酶 (PARP) 抑制剂的耐药性相关。 BRCA1 是一种核肿瘤抑制因子，对于通过同源重组 (HR) 解决双链 DNA 断裂 (DSB) 和链间交联 (ICL) 至关重要。体外动物和人类临床数据表明，BRCA1 缺陷型癌症对 ICL 诱导化疗药物高度敏感，适合利用 DSB/ICL 修复缺陷的合成致死方法，并且可能与提高生存率有关。相反，乳腺癌和卵巢癌中 BRCA1 的高表达或恢复表达与治疗耐药和不良预后相关。人们对鉴定干扰 BRCA1 依赖性 DSB/ICL 修复以恢复或增强对癌症治疗的敏感性的药物非常感兴趣。我们证明，热休克蛋白 90 (HSP90) 抑制剂 17-烯丙基氨基-17-去甲氧基格尔德霉素 [17-AAG (Tanespimycin)] 目前处于多种癌症的 II/III 期临床评估阶段，可诱导 BRCA1 泛素化和蛋白酶体降解，从而导致电离辐射和铂诱导的 DNA 损伤修复受损。我们发现，HSP90 功能的丧失会消除 BRCA1 依赖性 DSB 修复，并且由于 Gap 2/有丝分裂 (G2/M) 检查点激活受损以及由此产生的有丝分裂灾难，BRCA1 缺陷细胞对 17-AAG 高度敏感。总之，我们记录了 Fanconi 贫血/BRCA DSB/ICL 修复途径中的上游 HSP90 依赖性调节点，阐明了 BRCA1 在调节损伤相关检查点和对 HSP90 抑制剂的修复反应中的作用，并将 BRCA1 确定为增强难治性和/或耐药性恶性肿瘤敏感性的临床相关靶点。
Expression of functional breast cancer susceptibility gene 1 (BRCA1) in human breast and ovarian cancers is associated with resistance to platinum-based chemotherapeutics and poly(ADP ribose) polymerase (PARP) inhibitors. BRCA1 is a nuclear tumor suppressor that is critical for resolving double-strand DNA breaks (DSBs) and interstrand crosslinks (ICLs) by homologous recombination (HR). In vitro, animal and human clinical data have demonstrated that BRCA1-deficient cancers are highly sensitive to ICL-inducing chemotherapeutic agents, are amenable to synthetic lethal approaches that exploit defects in DSB/ICL repair, and may be associated with improved survival. Conversely, high or restored expression of BRCA1 in breast and ovarian cancer is associated with therapeutic resistance and poor prognosis. There has been much interest in identifying agents that interfere with BRCA1-dependent DSB/ICL repair to restore or enhance sensitivity to cancer therapeutics. We demonstrate that the heat-shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin [17-AAG (Tanespimycin)], currently in Phase II/III clinical evaluation for several cancers, induces BRCA1 ubiquitination and proteasomal degradation, resulting in compromised repair of ionizing radiation- and platinum-induced DNA damage. We show that loss of HSP90 function abolishes BRCA1-dependent DSB repair and that BRCA1-deficient cells are hypersensitive to 17-AAG due to impaired Gap 2/Mitosis (G2/M) checkpoint activation and resultant mitotic catastrophe. In summary, we document an upstream HSP90-dependent regulatory point in the Fanconi anemia/BRCA DSB/ICL repair pathway, illuminate the role of BRCA1 in regulating damage-associated checkpoint and repair responses to HSP90 inhibitors, and identify BRCA1 as a clinically relevant target for enhancing sensitivity in refractory and/or resistant malignancies.