Abstract
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. Li et al. demonstrate 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. CDC7-bound PGK1 under EGFR activation condition converts ADP to ATP, thereby abrogating ADP's inhibition on CDC7-ASK activity and promoting DNA replication.
Original language | English (US) |
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Pages (from-to) | 650-660.e8 |
Journal | Molecular cell |
Volume | 72 |
Issue number | 4 |
DOIs | |
State | Published - Nov 15 2018 |
Keywords
- ADP
- ASK
- CDC7
- CK2α
- DNA replication
- EGFR
- ERK1/2
- PGK1
- phosphorylation
- tumorigenesis
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology