Trp53-dependent DNA-repair is affected by the codon 72 polymorphism.
Trp53 is arguably the most critical tumour suppressor gene product that inhibits malignant transformation. Besides mutations that inactivate Trp53 functions, genetic polymorphisms have been suggested to be risk factors for cancer. A polymorphic site at codon 72 in exon 4 encodes either an arginine amino acid (Trp53(72R)) or a proline residue (Trp53(72P)). Previous studies have shown that the Trp53(72R) form is more efficient in apoptosis induction, whereas the Trp53(72P) form was suggested to induce G1 arrest better. Here we report that Trp53(72P) is more efficient than Trp53(72R) in specifically activating several Trp53-dependent DNA-repair target genes in several cellular systems. Moreover, using isogenic cell lines and several DNA-repair assays, we show that Trp53(72P) cells have a significantly higher DNA-repair capacity than the Trp53(72R) cells. Furthermore, Trp53(72P)-expressing cells exhibit reduced micronuclei formation compared to Trp53(72R)-expressing cells, suggesting that genomic instability is reduced in these cells. Together, the data highlight the functional differences between the Trp53 polymorphic variants, and suggest that their expression status may influence cancer risk.
Siddique
M
M
Laboratory of Molecular Carcinogenesis, National Cancer Centre, Singapore.
Sabapathy
K
K
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003062:Codon; D004260:DNA Repair / Q000235:genetics*; D006801:Humans; D011110:Polymorphism, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D003062:Codon; D016159:Tumor Suppressor Protein p53