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Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication, Mol Cell, 15 Nov 2018

发布时间:2018年11月15日

Molecular Cell, 15 November, 2018, DOI: https://doi.org/10.1016/j.molcel.2018.09.007

Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication

Xinjian Li, Xu Qian, Hongfei Jiang, Yan Xia, Yanhua Zheng, Jing Li, Bi-Jun Huang, Jing Fang, Chao-Nan Qian, Tao Jiang, Yi-Xin Zeng, Zhimin Lu

Summary

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 2α (CK2α) 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.

文章链接:https://www.sciencedirect.com/science/article/pii/S1097276518307548?via%3Dihub

 

 

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