The methyl methanesulfonate induced S-phase delay in XRCC1-deficient cells requires ATM and ATR.

Abstract	X-ray repair cross-complementing 1 (XRCC1) is required for DNA single-strand break and base excision repair (BER) in human cells. XRCC1-deficient human cells show hypersensitivity to cell killing, increased genetic instability and a significant delay in S-phase progression after exposure to the alkylating agent methyl methanesulfonate (MMS). Using RNAi modulation of XRCC1 levels, we show here that this S-phase delay is associated with significantly increased levels of recombinational repair as visualized by Rad51 focus formation. Using ATM- and ATR-defective cells and an ATM specific kinase inhibitor we demonstrate for the first time that the MMS-induced S-phase checkpoint requires both ATM and ATR. This unique dependency is associated with phosphorylation of ATM/ATR downstream targets or effectors such as SMC1 and Chk1. These results support the hypothesis that after MMS-treatment, the presence of unresolved BER intermediates gives rise to lesions that activate both ATM and ATR and that during the consequent S-phase delay, such intermediates may be repaired by a recombinational pathway which involves the Rad51 protein.
Authors	Reto Brem, Marie Fernet, Brigitte Chapot, Janet Hall
Journal	DNA repair (DNA Repair (Amst)) Vol. 7 Issue 6 Pg. 849-57 (Jun 01 2008) ISSN: 1568-7864 [Print] Netherlands
PMID	18375193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Cell Cycle Proteins DNA-Binding Proteins Tumor Suppressor Proteins X-ray Repair Cross Complementing Protein 1 XRCC1 protein, human Methyl Methanesulfonate ATM protein, human ATR protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases
Topics	Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins (metabolism, physiology) Cell Line, Tumor DNA-Binding Proteins (genetics, metabolism, physiology) Flow Cytometry Fluorescent Antibody Technique Humans Methyl Methanesulfonate (pharmacology) Phosphorylation Protein Serine-Threonine Kinases (metabolism, physiology) RNA Interference S Phase (drug effects) Signal Transduction Tumor Suppressor Proteins (metabolism, physiology) X-ray Repair Cross Complementing Protein 1

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