Quaternary structure of the specific p53-DNA complex reveals the mechanism of p53 mutant dominance
Aramayo, Ricardo and Sherman, M.B. and Brownless, K. and Lurz, R. and Okorokov, A.L. and Orlova, Elena (2011) Quaternary structure of the specific p53-DNA complex reveals the mechanism of p53 mutant dominance. Nucleic Acids Research 39 (20), pp. 8960-8971. ISSN 0305-1048.
The p53 tumour suppressor is a transcriptional activator that controls cell fate in response to various stresses. p53 can initiate cell cycle arrest, senescence and/or apoptosis via transactivation of p53 target genes, thus preventing cancer onset. Mutations that impair p53 usually occur in the core domain and negate the p53 sequence-specific DNA binding. Moreover, these mutations exhibit a dominant negative effect on the remaining wild-type p53. Here, we report the cryo electron microscopy structure of the full-length p53 tetramer bound to a DNA-encoding transcription factor response element (RE) at a resolution of 21 Å. While two core domains from both dimers of the p53 tetramer interact with DNA within the complex, the other two core domains remain available for binding another DNA site. This finding helps to explain the dominant negative effect of p53 mutants based on the fact that p53 dimers are formed co-translationally before the whole tetramer assembles; therefore, a single mutant dimer would prevent the p53 tetramer from binding DNA. The structure indicates that the Achilles’ heel of p53 is in its dimer-of-dimers organization, thus the tetramer activity can be negated by mutation in only one allele followed by tumourigenesis.
|Additional Information:||This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Nucleic Acids Research following peer review. The definitive publisher-authenticated version (Nucleic Acids Research 39(20), pp.8960-8971) is available online at: http://dx.doi.org/10.1093/nar/gkr386|
|School:||Birkbeck Schools and Departments > School of Science > Biological Sciences|
|Research Centre:||Structural Molecular Biology, Institute of (ISMB)|
|Date Deposited:||19 Apr 2012 16:54|
|Last Modified:||06 Dec 2016 11:13|
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