The ORFIUS complex regulates ORC2 localization at replication origins.
The ORFIUS complex regulates ORC2 localization at replication origins.
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高级别浆液性卵巢癌（HGSC）是一种致命的恶性肿瘤，具有升高的复制应激（RS）水平和缺陷的RS和RS相关的DNA损伤反应。在这里，我们证明了含溴结构域蛋白BRD 1是一种RS抑制蛋白，与组蛋白乙酰转移酶HBO 1（BRCA 1肿瘤抑制因子）和BARD 1（ORigin FIring Under Stress（ORFIUS））形成复制起点调控复合物。BRD 1和HBO 1通过支持起源许可蛋白ORC 2在起源处的定位来促进最终的起源激发。在BRD 1和/或HBO 1不存在的情况下，起源放电和具有ORC 2病灶的核都减少。BRCA 1调节BRD 1、HBO 1和ORC 2在复制起点的定位。在缺乏BRCA 1的情况下，起源放电和具有BRD 1、HBO 1和ORC 2病灶的核都增加。在正常和非HGSC卵巢癌细胞中，ORFIUS复合物响应ATR和CDC 7起源调节信号，并在RS期间脱离起源。在BRCA 1突变型和散发性HGSC细胞中，BRD 1、HBO 1和ORC 2仍然与复制起点相关，对RS、DNA损伤或起点调节激酶抑制无反应。ORFIUS复合物调节异常可能通过允许上调的起源放电和细胞周期进展而促进HGSC细胞存活，尽管积累了DNA损伤，并且可能是RS靶标。
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 BRCA1-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.