Please use this identifier to cite or link to this item: https://doi.org/10.1098/rsob.130138
Title: Xenopus Cdc7 executes its essential function early in S phase and is counteracted by checkpoint-regulated protein phosphatase 1
Authors: Poh, W.T
Chadha, G.S
Gillespie, P.J
Kaldis, P 
Blow, J.J
Keywords: 4 amino 7 tert butyl 5 (4 methylphenyl)pyrazolo[3,4 d]pyrimidine
CDC7 protein, Xenopus
cell cycle protein
enzyme inhibitor
etoposide
pha 767491
phosphoprotein phosphatase 1
piperidone derivative
protein serine threonine kinase
pyrrole derivative
Xenopus protein
animal
article
Cdc7
CHO cell line
chromatin
Cricetulus
DNA replication
drug antagonism
drug effect
enzymology
growth, development and aging
hamster
metabolism
oocyte
PHA-767491
phosphorylation
S phase cell cycle checkpoint
Xenopus
Cdc7
DNA replication
PHA-767491
PP1
Xenopus
Animals
Cell Cycle Proteins
CHO Cells
Chromatin
Cricetinae
Cricetulus
DNA Replication
Enzyme Inhibitors
Etoposide
Ovum
Phosphorylation
Piperidones
Protein Phosphatase 1
Protein-Serine-Threonine Kinases
Pyrroles
S Phase Cell Cycle Checkpoints
Xenopus
Xenopus Proteins
Issue Date: 2014
Citation: Poh, W.T, Chadha, G.S, Gillespie, P.J, Kaldis, P, Blow, J.J (2014). Xenopus Cdc7 executes its essential function early in S phase and is counteracted by checkpoint-regulated protein phosphatase 1. Open Biology 4 (JAN) : 130138. ScholarBank@NUS Repository. https://doi.org/10.1098/rsob.130138
Rights: Attribution 4.0 International
Abstract: The initiation of DNA replication requires two protein kinases: cyclin-dependent kinase (Cdk) and Cdc7. Although S phase Cdk activity has been intensively studied, relatively little is known about how Cdc7 regulates progression through S phase. We have useda Cdc7 inhibitor, PHA-767491, todissect the role of Cdc7 in Xenopus egg extracts. We show that hyperphosphorylation of mini-chromosome maintenance (MCM) proteins by Cdc7 is required for the initiation, but not for the elongation, of replication forks. Unlike Cdks, we demonstrate that Cdc7 executes its essential functions by phosphorylating MCM proteins at virtually all replication origins early in S phase and is not limiting for progression through the Xenopus replication timing programme. We demonstrate that protein phos-phatase 1 (PP1) is recruited to chromatin and rapidly reverses Cdc7-mediated MCM hyperphosphorylation. Checkpoint kinases induced by DNA damage or replication inhibition promote the association of PP1 with chromatin and increase the rate of MCM dephosphorylation, thereby counteracting the previously completed Cdc7 functions and inhibiting replication initiation. This novel mechanism for regulating Cdc7 function provides an explanation for previous contradictory results concerning the control of Cdc7 by checkpoint kinases and has implications for the use of Cdc7 inhibitors as anti-cancer agents. © 2014 The Authors.
Source Title: Open Biology
URI: https://scholarbank.nus.edu.sg/handle/10635/182031
ISSN: 20462441
DOI: 10.1098/rsob.130138
Rights: Attribution 4.0 International
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