An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication

Vincenzo Costanzo, David Shechter, Patrick J. Lupardus, Karlene A. Cimprich, Max Gottesman, Jean Gautier

Research output: Contribution to journalArticle

261 Citations (Scopus)

Abstract

We have analyzed how single-strand DNA gaps affect DNA replication in Xenopus egg extracts. DNA lesions generated by etoposide, a DNA topoisomerase II inhibitor, or by exonuclease treatment activate a DNA damage checkpoint that blocks initiation of plasmid and chromosomal DNA replication. The checkpoint is abrogated by caffeine and requires ATR, but not ATM, protein kinase. The block to DNA synthesis is due to inhibition of Cdc7/Dbf4 protein kinase activity and the subsequent failure of Cdc45 to bind to chromatin. The checkpoint does not require pre-RC assembly but requires loading of the single-strand binding protein, RPA, on chromatin. This is the biochemical demonstration of a DNA damage checkpoint that targets Cdc7/Dbf4 protein kinase.

Original languageEnglish (US)
Pages (from-to)203-213
Number of pages11
JournalMolecular Cell
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2003
Externally publishedYes

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DNA Replication
Protein Kinases
DNA Damage
Chromatin
DNA
Ataxia Telangiectasia Mutated Proteins
Topoisomerase II Inhibitors
Exonucleases
Etoposide
Xenopus
Caffeine
Ovum
Carrier Proteins
Plasmids

ASJC Scopus subject areas

  • Molecular Biology

Cite this

An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. / Costanzo, Vincenzo; Shechter, David; Lupardus, Patrick J.; Cimprich, Karlene A.; Gottesman, Max; Gautier, Jean.

In: Molecular Cell, Vol. 11, No. 1, 01.01.2003, p. 203-213.

Research output: Contribution to journalArticle

Costanzo, Vincenzo ; Shechter, David ; Lupardus, Patrick J. ; Cimprich, Karlene A. ; Gottesman, Max ; Gautier, Jean. / An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. In: Molecular Cell. 2003 ; Vol. 11, No. 1. pp. 203-213.
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