ATR kinase activation mediated by MutSα and MutLα in response to cytotoxic O6-methylguanine adducts

被引：233

作者：

Yoshioka, Ken-Ichi ^{[1
]}

Yoshioka, Yoshiko ^{[1
]}

Hsieh, Peggy ^{[1
]}

机构：

[1] NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA

来源：

MOLECULAR CELL | 2006年 / 22卷 / 04期

关键词：

D O I：

10.1016/j.molcel.2006.04.023

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

SO-type alkylating agents that produce cytotoxix 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 MutS alpha and MutL alpha. 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 MutSa 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 MutS alpha and MutL alpha-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.

引用

页码：501 / 510

页数：10

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