Abstract
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 ~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.
Highlights
Mutation of the gene encoding for p53—a transcription factor and one of the cell’s master tumor suppressors—is the most recurrent genetic alteration in human cancer [1,2]
Because p53 is inactivated in many cancers, such drugs would likely have broad clinical impact
It has been demonstrated that restoring proper function to mutant p53 is sufficient to kill a variety of tumors in mouse models [6,7,8]
Summary
Mutation of the gene encoding for p53—a transcription factor and one of the cell’s master tumor suppressors—is the most recurrent genetic alteration in human cancer [1,2]. The removal of Zn2+ elicits structural changes, in the loop that contains the DNA contact residue R248, that results in loss of DNA-binding specificity [22] It destabilizes DBD, causing it to cycle more rapidly between native and unfolded states [26]. It is true that mutations in the metal-binding pocket will almost certainly weaken zinc affinity, it is possible that other mutations may increase KdZn and be mistakenly assumed to belong to one of the other classes due to their distance from the zinc site This underscores the need to classify mutants based on functional and biophysical data as well as on structural location, as discussed below
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