Wild-type p53 negatively regulates hMSH2 expression by repressing promoter activity in normal human oral keratinocytes.

Abstract

Both p53 and hMSH2 are essential for maintaining genomic integrity, yet the regulatory link between them remains poorly understood. This study investigates the transcriptional repression of the DNA mismatch repair gene hMSH2 by wild-type p53 in normal human oral keratinocytes (NHOKs). We observed that inducing p53 with the alkylating agent led to a significant, time-dependent downregulation of hMSH2 mRNA and protein levels. Conversely, HPV-16-transformed oral keratinocytes, characterized by low p53 levels, exhibited dramatic overexpression of hMSH2 driven by a 27- to 38-fold increase in promoter activity. Transient transfection assays confirmed that wild-type p53 directly represses hMSH2 promoter activity, while antisense p53-mediated knockdown in NHOKs increased hMSH2 expression, mimicking the transformed phenotype. Sequencing of the hMSH2 5'-flanking region indicated that this regulation is mediated through trans-acting mechanisms rather than cis-acting mutations. These findings identify hMSH2 as a novel target of p53-mediated transcriptional repression and suggest that p53 may modulate mismatch repair capacity to coordinate the cellular decision between DNA repair and apoptosis in response to genotoxic stress.