A Meier-Gorlin syndrome mutation in a conserved C-terminal helix of Orc6 impedes origin recognition complex formation

摘要

Cell division is essential for organisms to be able to grow, to repair tissues and to proliferate. However, cells can only divide once they have successfully replicated their DNA. Many different molecules are involved in these two processes, including a large multi-protein assembly called the origin recognition complex that helps to start the process of DNA replication. This complex contains six proteins but relatively little is known about its structure. It is also unclear how much origin recognition complexes (ORCs) differ between species. Now, Bleichert et al. have found a way to stabilize a specific conformation of Drosophila ORC, and have gone on to determine its structure at a higher resolution than was previously possible. This approach revealed that the arrangement of protein subunits in Drosophila ORC is similar to that found in yeast ORC. Most of the ORC subunits have similar amino acid sequences in both species. However, the Orc6 subunit was regarded a notable exception for a long time, with the yeast and Drosophila versions of this subunit having different sequences of amino acids. Bleichert et al. show that the Orc6 subunits actually have important similarities, both in sequence and in function. In particular, the C-terminus of the Orc6 protein contains similar amino acids in both yeast and Drosophila. Moreover, it performs the same role—binding to another subunit—in both yeast and Drosophila. As well as being important for cell division, human ORC has been implicated in Meier-Gorlin syndrome, a type of dwarfism. Mutations in three of the six ORC subunits, including Orc6, have been found in people with Meier-Gorlin syndrome. The mutations in Orc6 that are associated with this syndrome are in the C-terminus, which suggests that some symptoms of the syndrome may be caused by DNA replication not being initiated correctly. Consistent with this idea, Bleichert et al. show that the introduction of the Meier-Gorlin syndrome mutation into Orc6 prevents this subunit from binding to the rest of ORC, and similar mutations do not support DNA replication in in vivo experiments. These results should increase our understanding of the function of Orc6 and its role in Meier-Gorlin syndrome, and also provide new insights into the changes in ORC architecture that have occurred during evolution.