Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Hypoxia promotes genetic instability by undefined mechanisms. The transcription factor HIF-1alpha is crucial for the cellular response to hypoxia and is frequently overexpressed in human cancers, resulting in the activation of genes essential for cell survival. Here, we demonstrate that HIF-1alpha is responsible for genetic instability at the nucleotide level by inhibiting MSH2 and MSH6, thereby decreasing levels of the MSH2-MSH6 complex, MutSalpha, which recognizes base mismatches. HIF-1alpha displaces the transcriptional activator Myc from Sp1 binding to repress MutSalpha expression in a p53-dependent manner; Sp1 serves as a molecular switch by recruiting HIF-1alpha to the gene promoter under hypoxia. Furthermore, in human sporadic colon cancers, HIF-1alpha overexpression is statistically associated with the loss of MSH2 expression, especially when p53 is immunochemically undetectable. These findings indicate that the regulation of DNA repair is an integral part of the hypoxic response, providing molecular insights into the mechanisms underlying hypoxia-induced genetic instability.

Original publication




Journal article


Mol Cell

Publication Date





793 - 803


Cell Hypoxia, Chromosomal Instability, Colonic Neoplasms, DNA Repair, DNA-Binding Proteins, Down-Regulation, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, MutS Homolog 2 Protein, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-myc, Sp1 Transcription Factor, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, Tumor Suppressor Protein p53