The nano-scale architecture of the nucleus

The post-reductionist era has been with us for some time, and cell biologists are now accomplished reconstructionists, building pictures of cellular structures from proteins identified through biochemistry and genetics. Understanding the beauty of cellular structures requires a knowledge of their inner architecture and engineering.A paper by Moir et al. addresses the process of DNA metabolism1xDisruption of nuclear lamin organization blocks the elongation phase of DNA replication. Moir, R.D. et al. J. Cell Biol. 2000; 149: 1179–1191Crossref | PubMed | Scopus (146)See all References1. Although we know much about the enzymes involved, many, many questions remain. The first of these is: on what scaffolding does DNA replication take place? DNA replication localizes to apparently immobile structures, so-called factories, that lie on the inner aspect of the nuclear membrane. This suggests that the synthesis of new DNA would require the feeding of chromatin through the factory and raises interesting questions of mechanical engineering. Is chromatin supported on either side of the factory, or does its weight drag it into the nuclear interior? Is the factory anchored in the nuclear membrane or to some other nuclear support? What engines drive chromatin through the factory – and how does the nucleus brace itself to withstand these forces?The foundation of nuclear envelope integrity has long been thought to be the nuclear lamina, and Moir et al. show clearly that, at least in Xenopus egg extracts, lamin structure is required for the elongation of replication forks. They find that the expression of a mutant human A-type lamin in the extracts leads to the formation of protein aggregates that include Xenopus lamins. These aggregates recruit at least two of the proteins (PCNA and RFC) involved in DNA replication. Because the initiation of DNA replication was not affected by lamina disruption, the authors suggest that normal lamin structure is required for the correct organization of elongation factors. This raises another question: why would the ubiquitous lamin proteins recruit elongation factors?One alternative explanation for the authors’ observations is that the aggregates are serving as a physical brake to the movement of the replication fork. Another idea is that the role of the lamina could simply be to withstand the mechanical forces generated by elongation rather than to serve as the bedrock foundation of the factory.The complexity of Millennium domes, Eiffel towers and ‘Ferris wheels’ are likely just pale reflections of life at the heart of the cell.