[HTML][HTML] ATR kinase activation mediated by MutSα and MutLα in response to cytotoxic O6-methylguanine adducts
K Yoshioka, Y Yoshioka, P Hsieh - Molecular cell, 2006 - cell.com
K Yoshioka, Y Yoshioka, P Hsieh
Molecular cell, 2006•cell.comSN 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 MutSα and MutLα. 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 MutSα 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 …
induce cell cycle arrest and apoptosis in a manner requiring the DNA mismatch repair
(MMR) proteins MutSα and MutLα. 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 MutSα 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 …
Summary
SN1-type alkylating agents that produce cytotoxic O6-methyl-G (O6-meG) DNA adducts induce cell cycle arrest and apoptosis in a manner requiring the DNA mismatch repair (MMR) proteins MutSα and MutLα. Here, we show that checkpoint signaling in response to DNA methylation occurs during S phase and requires DNA replication that gives rise to O6-meG/T mispairs. DNA binding studies reveal that MutSα specifically recognizes O6-meG/T mispairs, but not O6-meG/C. In an in vitro assay, ATR-ATRIP, but not RPA, is preferentially recruited to O6-meG/T mismatches in a MutSα- and MutLα-dependent manner. Furthermore, ATR kinase is activated to phosphorylate Chk1 in the presence of O6-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 O6-meG adducts to initiate ATR checkpoint signaling.
cell.com
