The bromodomain containing protein BRD-9 orchestrates RAD51-RAD54 complex formation and regulates homologous recombination-mediated repair
The bromodomain containing protein BRD-9 orchestrates RAD51-RAD54 complex formation and regulates homologous recombination-mediated repair
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含有溴结构域的蛋白 BRD-9 协调 RAD51-RAD54 复合物的形成并调节同源重组介导的修复
DOI：
10.1038/s41467-020-16443-x
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发表时间：
2020-05-26
影响因子：
16.6
通讯作者：
Yuan, Jian
中科院分区：
文献类型：
--
作者：
Zhou, Qin;Huang, Jinzhou;Yuan, Jian
同源重组对于DNA无差错双链断裂修复和维持基因组稳定性具有重要意义。然而，上调的HR也被癌细胞用来促进治疗抵抗。因此，诱导HR缺乏（HRD）是一种可行的策略，可以使HR熟练的癌症对DNA靶向治疗敏感，从而克服治疗耐药性。一种含有溴结构域的蛋白BRD9曾被报道调节染色质重塑和转录。在这里，我们发现DNA损伤后，BRD9的溴域结合在RAD54上的乙酰化K515，促进RAD54与RAD51的相互作用，这对HR至关重要。BRD9在卵巢癌中过度表达，耗尽BRD9会使癌细胞对奥拉帕尼和顺铂敏感。此外，BRD9抑制剂I-BRD9可与奥拉帕尼协同作用于hr精通型癌细胞。总的来说，我们的研究结果阐明了BRD9在HR中的作用，并确定BRD9是促进合成致死性和克服化疗耐药的潜在治疗靶点。含有溴结构域的蛋白BRD9已被报道调节染色质重塑和转录。在这里，作者揭示了BRD9通过促进RAD51-RAD54相互作用在同源重组中的作用。
Homologous recombination (HR) is important for error-free DNA double strand break repair and maintenance of genomic stability. However, upregulated HR is also used by cancer cells to promote therapeutic resistance. Therefore, inducing HR deficiency (HRD) is a viable strategy to sensitize HR proficient cancers to DNA targeted therapies in order to overcome therapeutic resistance. A bromodomain containing protein, BRD9, was previously reported to regulate chromatin remodeling and transcription. Here, we discover that following DNA damage, the bromodomain of BRD9 binds acetylated K515 on RAD54 and facilitates RAD54's interaction with RAD51, which is essential for HR. BRD9 is overexpressed in ovarian cancer and depleting BRD9 sensitizes cancer cells to olaparib and cisplatin. In addition, inhibitor of BRD9, I-BRD9, acts synergistically with olaparib in HR-proficient cancer cells. Overall, our results elucidate a role for BRD9 in HR and identify BRD9 as a potential therapeutic target to promote synthetic lethality and overcome chemoresistance. The bromodomain containing protein BRD9 has been reported to regulate chromatin remodeling and transcription. Here the authors reveal a role for BRD9 in homologous recombination by facilitating RAD51-RAD54 interaction.