The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways.
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:
Cell Cycle Proteins, Cell Line, DNA, Fanconi Anemia Complementation Group D2 Protein, Humans, Methoxsalen, Nuclear Proteins, Phosphorylation, Protein Kinases, Protein-Serine-Threonine Kinases, S Phase, Signal Transduction
Cell Cycle Proteins, Cell Line, DNA, Fanconi Anemia Complementation Group D2 Protein, Humans, Methoxsalen, Nuclear Proteins, Phosphorylation, Protein Kinases, Protein-Serine-Threonine Kinases, S Phase, Signal Transduction
EMBO J.
Date: Mar. 10, 2004
PubMed ID: 14988723
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