Fig. 1.
Proposed pathways how mutant p53 promotes aneuploidy, translocations, and amplifications by multiple gain-of-function mechanisms leading to genomic instability that ultimately promotes tumor growth and metastasis. Expression of mutant p53 in a normal or malignant cell inhibits TAp73, leading to a loss of BubR1 function, a spindle assembly checkpoint defect and aneuploidy. A direct interaction of mutant p53 with BubR1 is also possible. Certain p53 mutants may directly interact with centrosomes, possibly perturbing centrosome maintenance. Alternatively, binding and sequestration of Mre11 by mutant p53 prevents a double strand break checkpoint from occurring, which leads to inefficient DNA repair before cells enter mitosis. Furthermore, topoisomerase I activity is stimulated by p53 mutants, leading to an increase in recombinogenic events between chromosomes. Finally, telomere capping proteins may be inhibited by mutant p53 proteins, leading to loss of telomere protection and breakage—fusion bridge cycles generating chromosomal translocations.