کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1997822 1065620 2006 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
ATR Kinase Activation Mediated by MutSα and MutLα in Response to Cytotoxic O6-Methylguanine Adducts
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
ATR Kinase Activation Mediated by MutSα and MutLα in Response to Cytotoxic O6-Methylguanine Adducts
چکیده انگلیسی

SummarySN1-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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: - Volume 22, Issue 4, 19 May 2006, Pages 501–510
نویسندگان
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