PMID:16713580

Citation	Yoshioka, K, Yoshioka, Y and Hsieh, P (2006) ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts. Mol. Cell 22:501-10
Abstract	S(N)1-type alkylating agents that produce cytotoxic O(6)-methyl-G (O(6)-meG) DNA adducts induce cell cycle arrest and apoptosis in a manner requiring the DNA mismatch repair (MMR) proteins MutSalpha and MutLalpha. Here, we show that checkpoint signaling in response to DNA methylation occurs during S phase and requires DNA replication that gives rise to O(6)-meG/T mispairs. DNA binding studies reveal that MutSalpha specifically recognizes O(6)-meG/T mispairs, but not O(6)-meG/C. In an in vitro assay, ATR-ATRIP, but not RPA, is preferentially recruited to O(6)-meG/T mismatches in a MutSalpha- and MutLalpha-dependent manner. Furthermore, ATR kinase is activated to phosphorylate Chk1 in the presence of O(6)-meG/T mispairs and MMR proteins. These results suggest that MMR proteins can act as direct sensors of methylation damage and help recruit ATR-ATRIP to sites of cytotoxic O(6)-meG adducts to initiate ATR checkpoint signaling.
Links	PubMed PMC2423943 Online version:10.1016/j.molcel.2006.04.023
Keywords	Adaptor Proteins, Signal Transducing; Animals; Base Pair Mismatch; Base Sequence; Carrier Proteins/metabolism; Cell Cycle Proteins/metabolism; Cell Line; DNA/genetics; DNA/metabolism; DNA Adducts/metabolism; DNA Adducts/toxicity; DNA Damage; DNA Repair/physiology; DNA-Binding Proteins; Enzyme Activation/drug effects; Exodeoxyribonucleases/metabolism; Guanine/analogs & derivatives; Guanine/metabolism; HeLa Cells; Humans; Mice; MutS DNA Mismatch-Binding Protein/metabolism; Nuclear Proteins/metabolism; Phosphoproteins/metabolism; Protein-Serine-Threonine Kinases/metabolism; S Phase; Signal Transduction
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