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ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts.
- Source :
-
Molecular cell [Mol Cell] 2006 May 19; Vol. 22 (4), pp. 501-10. - Publication Year :
- 2006
-
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.
- Subjects :
- Adaptor Proteins, Signal Transducing
Animals
Ataxia Telangiectasia Mutated Proteins
Base Pair Mismatch
Base Sequence
Carrier Proteins metabolism
Cell Line
DNA genetics
DNA metabolism
DNA Adducts toxicity
DNA Damage
DNA-Binding Proteins
Enzyme Activation drug effects
Exodeoxyribonucleases metabolism
Guanine metabolism
HeLa Cells
Humans
Mice
Nuclear Proteins metabolism
Phosphoproteins metabolism
S Phase
Signal Transduction
Cell Cycle Proteins metabolism
DNA Adducts metabolism
DNA Repair physiology
Guanine analogs & derivatives
MutS DNA Mismatch-Binding Protein metabolism
Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-2765
- Volume :
- 22
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 16713580
- Full Text :
- https://doi.org/10.1016/j.molcel.2006.04.023