Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication
Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication
复制标题
核PGK1减轻CDC7的ADP依赖性抑制以促进DNA复制
DOI：
10.1016/j.molcel.2018.09.007
复制
发表时间：
2018-11-15
期刊：
影响因子：
16
通讯作者：
Lu, Zhimin
中科院分区：
文献类型：
--
作者：
Li, Xinjian;Qian, Xu;Lu, Zhimin
DNA复制是由激酶细胞分裂周期7（CDC 7）与其调节激活亚基（S期激酶激活剂（ASK））组装启动，以激活DNA解旋酶。然而，CDC 7-ASK复合物的调节机制尚不清楚。在这里，我们表明，ADP产生的CDC 7介导的MCM磷酸化结合到CDC 7的变构区域，破坏CDC 7-ASK相互作用，并抑制CDC 7-ASK活性的反馈方式。EGFR和ERK激活的酪蛋白激酶2 α（CK 2 α）在S256处磷酸化核磷酸甘油酸激酶（PGK）1，导致PGK 1与CDC 7相互作用。CDC 7结合的PGK 1将ADP转化为ATP，从而消除ADP对CDC 7-ASK活性的抑制作用，促进DNA解旋酶向复制起点的募集、DNA复制、细胞增殖和脑肿瘤发生。这些发现揭示了CDC 7-ASK活性通过其激酶反应产物ADP的自我调节机制，以及PGK 1在消除促进肿瘤发展的负反馈中的非糖溶作用。
DNA replication is initiated by assembly of the kinase cell division cycle 7 (CDC7) with its regulatory activation subunit, activator of S-phase kinase (ASK), to activate DNA helicase. However, the mechanism underlying regulation of CDC7-ASK complex is unclear. Here, we show that ADP generated from CDC7-mediated MCM phosphorylation binds to an allosteric region of CDC7, disrupts CDC7-ASK interaction, and inhibits CDC7-ASK activity in a feedback way. EGFR- and ERK-activated casein kinase 2 alpha (CK2 alpha) phosphorylates nuclear phosphoglycerate kinase (PGK) 1 at S256, resulting in interaction of PGK1 with CDC7. CDC7-bound PGK1 converts ADP to ATP, thereby abrogating the inhibitory effect of ADP on CDC7-ASK activity, promoting the recruitment of DNA helicase to replication origins, DNA replication, cell proliferation, and brain tumorigenesis. These findings reveal an instrumental self-regulatory mechanism of CDC7-ASK activity by its kinase reaction product ADP and a nonglycolytic role for PGK1 in abrogating this negative feedback in promoting tumor development.