p53 Binds and activates the xeroderma pigmentosum DDB2 gene in humans but not mice.
The DDB2 gene, which is mutated in xeroderma pigmentosum group E, enhances global genomic repair of cyclobutane pyrimidine dimers and suppresses UV-induced mutagenesis. Because DDB2 transcription increases after DNA damage in a p53-dependent manner, we searched for and found a region in the human DDB2 gene that binds and responds transcriptionally to p53. The corresponding region in the mouse DDB2 gene shared significant sequence identity with the human gene but was deficient for p53 binding and transcriptional activation. Furthermore, when mouse cells were exposed to UV, DDB2 transcription remained unchanged, despite the accumulation of p53 protein. These results demonstrate direct activation of the human DDB2 gene by p53. They also explain an important difference in DNA repair between humans and mice and show how mouse models can be improved to better reflect cancer susceptibility in humans.
Tan
Thomas
T
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305-5151, USA.
Chu
Gilbert
G
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology* / Q000528:radiation effects; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020218:Response Elements / Q000235:genetics*; D014158:Transcription, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects; D014983:Xeroderma Pigmentosum / Q000235:genetics* / Q000378:metabolism
C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53