Dimers, Tetramers, and DNA – Oh my.

REFERENCE:  Aramayo et al. Nucleic Acids Research (2011) 
                        Epub ahead of print: July 14^th, 2011

The tumor suppressor p53 transactivates genes involved in cell cycle arrest, apoptosis or senescence.  Several key papers have established p53’s structure as a dimer of dimers.  The central core domain, where the majority of cancerous mutations reside, is responsible for sequence specific binding to DNA.  Despite years of structural work, several questions, including the spatial arrangement of all p53’s domains and the basis for dominant negative p53 mutant effects, remain.  A recent paper by Aramayo et al. discusses a 21 Å cryo electron microscopy structure where full length murine p53 is bound to DNA duplexes bearing consecutive p53 recognition elements (REs).  Their data suggests that only one core domain of each dimer binds to an RE while the other two core domains remain unoccupied.  This type of complex requires a ~ 45° rotation of one dimer relative to the other upon DNA binding, a movement which is notable in other DNA binding proteins.  This rotation also allows for the C terminal domains, known to bind DNA nonspecifically, to come in contact with the duplex, while the N terminal domains become poised for interaction with the replication machinery.  It was previously established that p53 dimers are formed co-translationally while tetramers are formed post-translationally.  One allele bearing a core domain mutation will lead to dimers where each subunit bears the mutation.  This information, along with the described structure, offers a mechanistic explanation for why one mutated allele leads to dominant negative effects in p53 function: with one mutated allele, 75% of the p53 tetramers will be unable to bind DNA.