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

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? (CK2?) 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.
Mesh Terms:
Adenosine Diphosphate, Animals, Casein Kinase II, Cell Cycle Proteins, Cell Line, Cell Line, Tumor, DNA Helicases, DNA Replication, Female, Heterografts, Humans, MAP Kinase Signaling System, Mice, Mice, Inbred BALB C, Mice, Nude, Phosphoglycerate Kinase, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Replication Origin
Mol. Cell
Date: Dec. 15, 2017
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