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

Mol Cell. 2018 Nov 15;72(4):650-660.e8. doi: 10.1016/j.molcel.2018.09.007. Epub 2018 Nov 1.


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.

Keywords: ADP; ASK; CDC7; CK2α; DNA replication; EGFR; ERK1/2; PGK1; phosphorylation; tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Diphosphate / metabolism*
  • Animals
  • Casein Kinase II / genetics
  • Casein Kinase II / metabolism*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology
  • Cell Line
  • Cell Line, Tumor
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA Replication*
  • Female
  • Heterografts
  • Humans
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphoglycerate Kinase / genetics
  • Phosphoglycerate Kinase / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Serine-Threonine Kinases / physiology
  • Replication Origin


  • Cell Cycle Proteins
  • DBF4 protein, human
  • Adenosine Diphosphate
  • CDC7 protein, human
  • Casein Kinase II
  • Protein Serine-Threonine Kinases
  • PGK1 protein, human
  • Phosphoglycerate Kinase
  • DNA Helicases