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PMID: 14988723 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways.

The EMBO journal ·Vol. 23 ·No. 5 ·2004-03-10 ·Pages 1178-87

Pichierri P, Rosselli F

Abstract

The genetic syndrome Fanconi anemia (FA) is characterized by aplastic anemia, cancer predisposition and hypersensitivity to DNA interstrand crosslinks (ICLs). FA proteins (FANCs) are thought to work in pathway(s) essential for dealing with crosslinked DNA. FANCs interact with other proteins involved in both DNA repair and S-phase checkpoint such as BRCA1, ATM and the RAD50/MRE11/NBS1 (RMN) complex. We deciphered the previously undefined pathway(s) leading to the ICLs-induced S-phase checkpoint and the role of FANCs in this process. We found that ICLs activate a branched pathway downstream of the ATR kinase: one branch depending on CHK1 activity and the other on the FANCs-RMN complex. The transient slow-down of DNA synthesis was abolished in cells lacking ATR, whereas CHK1-siRNA-treated cells, NBS1 or FA cells showed partial S-phase arrest. CHK1 RNAi in NBS1 or FA cells abolished the S-phase checkpoint, suggesting that CHK1 and FANCs/NBS1 proteins work on parallel pathways. Furthermore, we found that ICLs trigger ATR-dependent FANCD2 phosphorylation and FANCD2/ATR colocalization. This study demonstrates a novel relationship between the FA pathway(s) and the ATR kinase.

MeSH Terms
Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/genetics,metabolism Cell Line Checkpoint Kinase 1 DNA/metabolism Fanconi Anemia Complementation Group D2 Protein Humans Methoxsalen/pharmacology Nuclear Proteins/genetics,metabolism Phosphorylation/drug effects Protein Kinases/genetics,metabolism Protein Serine-Threonine Kinases/genetics,metabolism S Phase Signal Transduction/drug effects
Chemicals
Cell Cycle Proteins FANCD2 protein, human Fanconi Anemia Complementation Group D2 Protein NBN protein, human Nuclear Proteins DNA Protein Kinases ATR protein, human Ataxia Telangiectasia Mutated Proteins CHEK1 protein, human Checkpoint Kinase 1 Protein Serine-Threonine Kinases Methoxsalen
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Pichierri Pietro
UPR 2169 du CNRS, Institut Gustave Roussy PR2, Villejuif Cedex, France.
Rosselli Filippo
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7600113
Published
2004-03-10
Epub
2004-00-26
Pages
1178-87
Language
English
Region
England
NLM ID
8208664
PMCID
PMC380971
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.emboj.7600113 PMC Full Text View journal details
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