MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation.
The mismatch repair proteins function upstream in the DNA damage signaling pathways induced by the DNA methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). We report that MSH2 (MutS homolog 2) protein interacts with the ATR (ATM- and Rad3-related) kinase to form a signaling module and regulate the phosphorylation of Chk1 and SMC1 (structure maintenance of chromosome 1). We found that phosphorylation of Chk1 by ATR also requires checkpoint proteins Rad17 and replication protein A. In contrast, phosphorylation of SMC1 by ATR is independent of Rad17 and replication protein A, suggesting that the signaling pathway leading to SMC1 phosphorylation is distinct from that mediated by the checkpoint proteins. In addition, both MSH2 and Rad17 are required for the activation of the S-phase checkpoint to suppress DNA synthesis in response to MNNG, and phosphorylation of SMC1 is required for cellular survival. These data support a model in which MSH2 and ATR function upstream to regulate two branches of the response pathway to DNA damage caused by MNNG.
Wang
Yi
Y
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Qin
Jun
J
D064007:Ataxia Telangiectasia Mutated Proteins; D020137:Base Pair Mismatch; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology*; D051718:MutS Homolog 2 Protein; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D008769:Methylnitronitrosoguanidine; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein