Start as you mean to go on

In Nature Structural & Molecular Biology, two papers now show that the core machinery that initiates DNA replication has a conserved structure in all domains of life (archaea, bacteria and eukarya). Initiators, which belong to the AAA+ (ATPases associated with various cellular activities) family of proteins, drive DNA remodelling at replication origins. Structural insights into initiators in bacteria and eukaryotes have now been provided by Berger, Botchan, Nogales and colleagues.

In the first paper, the Berger group describes a crystal structure of the initiator protein DnaA from Aquifex aeolicus bound to a non-hydrolysable ATP analogue. Rather than forming an oligomeric closed-ring structure, as has been seen for most AAA+ proteins so far, the DnaA monomers form an oligomeric right-handed superhelix. This structure indicates how DnaA binds and unwinds replication origins, and also indicates that other regulatory AAA+ proteins can bind to the exposed ends of the DnaA superhelix. In the second paper, Botchan, Nogales, Berger and co-workers present electron-microscopy reconstructions of the Drosophila melanogaster origin recognition complex (ORC). Docking a DnaA–'ATP' helical pentamer into the ORC reconstructions revealed a good fit, which indicates that a right-handed superhelix also forms the core of the eukaryotic initiation complex. Together with previous work in archaea, these studies indicate “...strong mechanistic commonalities in the ways that initiators engage and remodel replication origins....” ORIGINAL RESEARCH PAPERS Erzberger, J. P. et al. Structural basis for ATP-dependent DnaA assembly and replication-origin remodeling. Nature Struct. Mol. Biol. 13676–683 (2006) Clarey, M. G. et al. Nucleotide-dependent conformational changes in the DnaA-like core of the origin recognition complex. Nature Struct. Mol. Biol. 13684–690 (2006)

A dimer of dimers

p53 binds to DNA as a homotetramer to control the transcription of genes that mediate cellular stress responses. Although important insights into p53–DNA binding were provided over a decade ago by a structure of a p53 DNA-binding core domain (p53DBD) monomer bound to DNA, many questions remained. However, new insights into this interaction have now been provided by Marmorstein and colleagues in The Journal of Biological Chemistry.

The authors managed to obtain a crystal structure of a p53DBD dimer bound to DNA by using a crosslinking strategy. The overall protein fold and the DNA contacts are similar to those seen previously. However, this structure shows that the p53DBDs dimerize through their zinc-binding domains over the central DNA minor groove, and it seems that this dimerization interface is a hot spot for cancer-related mutations. Furthermore, the structure enabled the authors to model a dimer of p53DBD dimers bound to DNA, which indicates that dimer–dimer contacts are less frequently mutated in human cancers than intra-dimer contacts. ORIGINAL RESEARCH PAPER Ho, W. C. et al. Structure of the p53 core domain dimer bound to DNA. J. Biol. Chem. 28120494–20502 (2006)