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

HERC2是一种E3泛素连接酶，针对乳腺癌抑制基因BRCA1进行降解。在这里，我们证明了HERC2是DNA复制叉复合体的一个组成部分，它在DNA伸长和起始点火中起着关键作用。在BRCA1存在的情况下，HERC2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缺失减缓了S期的衰退，额外的HERC2缺失降低了Claspin缺失的影响。HERC2与复制叉复合体蛋白相互作用。HERC2的缺失缓解了Claspin缺陷细胞中缓慢的复制分叉进程，抑制了增强的起始激发。在复制应激反应中，HERC2在ATrip复合体中的数量增加，导致ATR增加MCM2的磷酸化。HERC2、Claspin和BRCA1可能在Chk1和Plk1的激活上协同作用，通过促进MCM2的磷酸化来调节DNA复制进程和起始激发。

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.