Journal
BIOMOLECULES
Volume 10, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/biom10020303
Keywords
folding; stability; structure; zinc binding; DNA binding; metallochaperone; aggregation; tumor suppressor; cancer
Categories
Funding
- National Institutes of Health [R01 CA200800]
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The mutational landscape of p53 in cancer is unusual among tumor suppressors because most of the alterations are of the missense type and localize to a single domain: the similar to 220 amino acid DNA-binding domain. Nearly all of these mutations produce the common effect of reducing p53's ability to interact with DNA and activate transcription. Despite this seemingly simple phenotype, no mutant p53-targeted drugs are available to treat cancer patients. One of the main reasons for this is that the mutations exert their effects via multiple mechanisms-loss of DNA contacts, reduction in zinc-binding affinity, and lowering of thermodynamic stability-each of which involves a distinct type of physical impairment. This review discusses how this knowledge is informing current efforts to develop small molecules that repair these defects and restore function to mutant p53. Categorizing the spectrum of p53 mutations into discrete classes based on their inactivation mechanisms is the initial step toward personalized cancer therapy based on p53 allele status.
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