The role of BRCA1-HERC2 complex in DNA replication fork progression and stress response

HERC 2是一种E3泛素连接酶，靶向乳腺癌抑制因子BRCA 1进行降解。在这里，我们表明，HERC 2是DNA复制叉复合物的一个组成部分，在DNA延伸和起点发射中起着至关重要的作用。在BRCA 1存在的情况下，HERC 2与Claspin相互作用，Claspin是G2/M检查点激活和复制叉稳定性所必需的蛋白质。Claspin消耗减缓S期进展，并且额外的HERC 2消耗降低Claspin消耗的作用。HERC 2与复制叉复合物蛋白相互作用。HERC 2的消耗减轻了Claspin缺陷细胞中缓慢的复制叉进展，抑制了增强的起点放电。在复制应激反应期间，ATRIP复合物中HERC 2的量增加，导致ATR引起的MCM 2磷酸化增加。HERC 2、Claspin和BRCA 1可能通过促进MCM 2磷酸化来协同激活Chk 1和Plk 1以调节DNA复制进程和起始点激发。

HERC2 is an E3 ubiquitin ligase that targets breast cancer suppressor BRCA1 for degradation. Here we show that HERC2 is a component of the DNA replication fork complex that plays a critical role in DNA elongation and origin firing. In the presence of BRCA1, HERC2 interacts with Claspin, a protein essential for G2/M checkpoint activation and replication fork stability. Claspin depletion slowed S-phase rogression and additional HERC2 depletion reduced the effect of Claspin depletion. HERC2 interacts with replication fork complex proteins. Depletion of HERC2 alleviated the slow replication fork progression in Claspin-deficient cells, suppressed enhanced origin firing. During replication stress response, the amount of HERC2 is increased in the ATRIP complex, to result in an increase of MCM2 phosphorylation by ATR. HERC2, Claspin, and BRCA1 possibly cooperate on activation of Chk1 and Plk1 to regulate DNA replication progression and origin firing by facilitating MCM2 phosphrylation.