Dissection of the sequence-specific DNA binding and exonuclease activities reveals a superactive yet apoptotically impaired mutant p53 protein
2009
Both sequence-specific DNA binding and exonuclease activities have been mapped to the central conserved core domain of p53. To gain more information about these two activities a series of mutants were generated that changed core domain histidine residues. Of these mutants, only one, H115N p53, showed markedly reduced exonuclease activity (ca. 15% of wild-type). Surprisingly, purified H115N p53 protein was found to be significantly more potent than wild-type p53 in binding to DNA by several criteria including gel mobility shift assay, filter binding and DNase I footprinting. Interestingly as well, non-specific DNA binding by the core domain of H115N p53 is superior to that of wild-type p53. To study H115N p53 in vivo, clones of H1299 cells expressing tetracycline regulated wild-type or H115N p53 were generated. H115N was both more potent than wild-type p53 in inducing p53 target genes such as p21 and PIG3 and was also more effective in arresting cells in G1. Unexpectedly, in contrast to wild-type p53...
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