Disrupting the chromatin–nuclear envelope link (bottom) prevents DNA replication initiation.

The nuclear envelope clearly helps regulate eukaryotic DNA replication, but many of the molecular pieces of this process are still unknown. On page 177, Martins et al. describe a novel, direct interaction between the nuclear envelope and the genome, mediated by the inner nuclear membrane protein LAP2b and the nuclear matrix–associated protein HA95, that is required for the initiation of replication.

Having cloned HA95 two years ago, the authors now find that it interacts with LAP2b through two distinct domains. Abolishing the HA95–LAP2b interaction leads to the proteasome-mediated breakdown of prereplication complex component Cdc6, and a block in replication initiation. The HA95–LAP2b interaction is not required for DNA replication elongation or nuclear envelope reassembly after mitosis.The results add to the growing list of functions for HA95, which is also required for normal nuclear envelope breakdown and chromatin condensation, and is believed to facilitate the export of unspliced viral RNA from the nucleus. In replication initiation, HA95 probably works by protecting the prereplication complex from degradation. Martins et al. propose that the global distribution of HA95 in the nucleus and its ability to bind multiple ligands may explain why it appears in several critical regulatory pathways. ▪