Yang Zelei, Mogre Saie, He Ruiyang, Berdan Emma L, Ho Sui Shannan J, Hill Sarah J
Department of Medical Oncology and Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Harvard Chan Bioinformatics Core, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
NAR Cancer. 2024 Jan 29;6(1):zcae003. doi: 10.1093/narcan/zcae003. eCollection 2024 Mar.
High-grade serous ovarian cancer (HGSC) is a lethal malignancy with elevated replication stress (RS) levels and defective RS and RS-associated DNA damage responses. Here we demonstrate that the bromodomain-containing protein BRD1 is a RS suppressing protein that forms a replication origin regulatory complex with the histone acetyltransferase HBO1, the BRCA1 tumor suppressor, and BARD1, ORigin FIring Under Stress (ORFIUS). BRD1 and HBO1 promote eventual origin firing by supporting localization of the origin licensing protein ORC2 at origins. In the absence of BRD1 and/or HBO1, both origin firing and nuclei with ORC2 foci are reduced. BRCA1 regulates BRD1, HBO1, and ORC2 localization at replication origins. In the absence of BRCA1, both origin firing and nuclei with BRD1, HBO1, and ORC2 foci are increased. In normal and non-HGSC ovarian cancer cells, the ORFIUS complex responds to ATR and CDC7 origin regulatory signaling and disengages from origins during RS. In -mutant and sporadic HGSC cells, BRD1, HBO1, and ORC2 remain associated with replication origins, and unresponsive to RS, DNA damage, or origin regulatory kinase inhibition. ORFIUS complex dysregulation may promote HGSC cell survival by allowing for upregulated origin firing and cell cycle progression despite accumulating DNA damage, and may be a RS target.
高级别浆液性卵巢癌（HGSC）是一种致命的恶性肿瘤，其复制应激（RS）水平升高，且RS及与RS相关的DNA损伤反应存在缺陷。在此我们证明，含溴结构域蛋白BRD1是一种RS抑制蛋白，它与组蛋白乙酰转移酶HBO1、BRCA1肿瘤抑制因子和BARD1（应激下的起始点激发因子，ORFIUS）形成复制起始点调节复合物。BRD1和HBO1通过支持起始点许可蛋白ORC2在起始点的定位来促进最终的起始点激发。在缺乏BRD1和/或HBO1的情况下，起始点激发以及含有ORC2焦点的细胞核数量均减少。BRCA1调节BRD1、HBO1和ORC2在复制起始点的定位。在缺乏BRCA1的情况下，起始点激发以及含有BRD1、HBO1和ORC2焦点的细胞核数量均增加。在正常和非HGSC卵巢癌细胞中，ORFIUS复合物对ATR和CDC7起始点调节信号作出反应，并在RS期间从起始点脱离。在突变型和散发性HGSC细胞中，BRD1、HBO1和ORC2仍与复制起始点相关，且对RS、DNA损伤或起始点调节激酶抑制无反应。ORFIUS复合物失调可能通过允许尽管存在累积的DNA损伤但仍上调起始点激发和细胞周期进程来促进HGSC细胞存活，并且可能是一个RS靶点。
