Work

MLH1- and ATM-dependent MAPK Signaling Is Activated through c-Abl in Response to the Alkylator N-Methyl-N′-nitro-N′-nitrosoguanidine

Year: 2007

Type: article

Abstract: N-Methyl-N'-nitro-N'-nitrosoguanidine (MNNG) is a DNA-methylating agent, and deficiency in mismatch repair (MMR) results in lack of sensitivity to this genotoxin (termed alkylation tolerance). A number of DNA damage response pathways are activated in a MMR-dependent manner following MNNG, and several also require ATM kinase activity. Here we show that activation of the transcription factor c-Jun is dependent upon both the MMR component MLH1 and ATM, but not ATR, in response to MNNG. In addition to c-Jun, the upstream MAPKs JNK and MKK4 are also activated in a MLH1- and ATM-dependent manner. We document that c-Jun activation is dependent on the MAPK kinase kinase MEKK1. Additionally, the tyrosine kinase c-Abl is required to activate this signaling cascade and forms a complex with MEKK1 and MLH1. This study indicates that an arm of DNA damage-activated MAPK signaling is activated in an MLH1- and ATM-dependent manner in response to MNNG and perhaps suggests that dysregulation of this signaling is responsible, in part, for alkylation tolerance.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m701451200

Authors: Wan-Ju Kim, Baskaran Rajasekaran, Kevin D. Brown

Institutions: University of Florida Health, University of Florida, UF Health Cancer Center, University of Pittsburgh Medical Center

Language: English

Topic: DNA Repair Mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,430