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PMID: 11030344 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Reconstitution of an ATM-dependent checkpoint that inhibits chromosomal DNA replication following DNA damage.

Molecular cell ·Vol. 6 ·No. 3 ·2000-09-00 ·Pages 649-59

Costanzo V, Robertson K, Ying CY, Kim E, Avvedimento E, Gottesman M, Grieco D, Gautier J

Abstract

Cell cycle checkpoints lead to the inhibition of cell cycle progression following DNA damage. A cell-free system derived from Xenopus eggs has been established that reconstitutes the checkpoint pathway inhibiting DNA replication initiation. DNA containing double-strand breaks inhibits replication initiation in a dose-dependent manner. Upon checkpoint activation, a prereplicative complex is assembled that contains ORC, Cdc6, Cdc7, and MCM proteins but lacks Cdc45. The checkpoint is ATM dependent. Cdk2/CyclinE acts downstream of ATM and is downregulated by Cdk2 phosphorylation on tyrosine 15. Cdk2AF/CyclinE is refractory to checkpoint signaling, and Cdc25A overrides the checkpoint and restores DNA replication. This report provides the description of a DNA damage checkpoint pathway that prevents the onset of S phase independently of the transcriptional function of p53 in a vertebrate organism.

MeSH Terms

Androstadienes/pharmacology Animals Ataxia Telangiectasia Mutated Proteins CDC2-CDC28 Kinases Caffeine/pharmacology Carrier Proteins/metabolism Cell Cycle Proteins Cell-Free System Chromosomes/genetics Cyclin E/metabolism Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases/genetics,metabolism DNA/genetics DNA Damage/physiology DNA Replication/drug effects,physiology DNA-Binding Proteins Enzyme Inhibitors/pharmacology Male Mutagenesis/physiology Nuclear Proteins/metabolism Oocytes Phosphodiesterase Inhibitors/pharmacology Phosphorylation Protein Serine-Threonine Kinases/genetics,metabolism Replication Origin/physiology S Phase/genetics Saccharomyces cerevisiae Proteins Signal Transduction/physiology Spermatozoa Transcription, Genetic/genetics Tumor Suppressor Proteins Tyrosine/metabolism Wortmannin Xenopus Xenopus Proteins

Chemicals

Androstadienes CDC45 protein, S cerevisiae Carrier Proteins Cell Cycle Proteins Cyclin E DNA-Binding Proteins Enzyme Inhibitors Nuclear Proteins Phosphodiesterase Inhibitors Saccharomyces cerevisiae Proteins Tumor Suppressor Proteins Xenopus Proteins Caffeine Tyrosine DNA Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases CDC2-CDC28 Kinases Cdk2 protein, Xenopus Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases Wortmannin

Authors & Affiliations

8 authors, click to expand affiliations / ORCID

Costanzo V

Department of Genetics and Development, Columbia University, New York, NY 10032, USA.

Robertson K

Ying C Y

Kim E

Avvedimento E

Gottesman M

Grieco D

Gautier J

Article Info

Journal

Molecular cell

Abbr.

Mol Cell

ISSN

1097-2765

DOI

10.1016/s1097-2765(00)00063-0

Published

2000-09-00

Pages

649-59

Language

English

Region

United States

NLM ID

9802571

Subset

Grants

NIGMS NIH HHS · R01GM56781 · United States

External Links

PubMed source DOI: 10.1016/s1097-2765(00)00063-0 View journal details

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Reconstitution of an ATM-dependent checkpoint that inhibits chromosomal DNA replication following DNA damage.

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