Shumaker et al. A conserved lamin domain, the group shows, positions a DNA polymerase processivity factor on chromatin.
The lamins are self-assembling proteins that create a network of intermediate filaments around the inner membrane of the nuclear envelope. Lamins are also found in the nucleoplasm, where their structure is uncertain. The new findings suggest that some of these nonenvelope lamins create a docking site for PCNA, which helps clamp DNA polymerase onto the genome.
PCNA and lamin B were previously shown to colocalize during S phase. The authors now reveal that PCNA hooks on via lamin's highly conserved Ig-fold motif. In vitro, formation of a lamin network preceded PCNA localization to chromatin. Flooding the cell with lamin Ig fragments hindered DNA replication in HeLa cells and in nuclei assembled in vitro, most likely by displacing PCNA from the chromatin. Whether the interaction with lamins also activates PCNA is not yet clear.
Some lamin isoforms held more tightly to PCNA than others, apparently due to the presence of longer C-terminal tail regions just past the Ig-fold. The authors suggest that the tail may fold back and stabilize any Ig–PCNA interactions.
The Ig-fold motif is ideal for protein–protein interactions and seems to harbor additional sites for many binding partners, including nucleic acids and other lamins. PCNA that has bound to lamin might thus encounter other partners important for DNA synthesis, such as replication factor C.
Although it is just ∼100–amino acids long, the lamin Ig-fold is a hotspot for mutations that cause a class of human diseases known as laminopathies. One such mutation, which causes Emery-Dreifuss muscular dystrophy, weakened the lamin–PCNA interactions. Whether this disease stems from DNA replication defects and why such defects would mainly affect muscle cells remain to be seen.