Torsin ATPases influence chromatin interaction of the Torsin regulator LAP1
A recent eLife publication by the Kutay group shows that the inner nuclear membrane protein LAP1 is a novel chromatin-binding factor that fails to be released from mitotic chromatin if the functionality of Torsin ATPases is compromised, inducing chromosome segregation defects and binucleation.
The inner nuclear membrane (INM) closely interacts with nuclear partners to protect and organize the eukaryotic genome. These interactions are broken during cell division to allow for the faithful segregation of the genome into daughter cells. The precise mechanisms required for dissolving INM protein-chromatin contacts remain to be elucidated. Here, we show that increased levels of the abundant INM protein LAP1 or loss of Torsin functionality result in persistent tethering of membranes to chromatin during mitosis, accompanied by chromosome missegregation and severe nuclear aberrations. Together with the Fierz lab at EPFL, we establish that LAP1 is a novel chromatin-associated factor at the INM that binds DNA directly.
LAP1 is a known activator of the Torsin AAA+-ATPases and mutations in both LAP1 and Torsins have been implicated in Torsion dystonia. Although Torsins have been intensively studies over the last years, their substrate remains unknown. Unexpectedly, we find that overexpression of wildtype, but not ATPase deficient Torsins rescues LAP1-induced nuclear aberrations. In converse, an ATPase-deficient Torsin induces binucleation in a LAP1-dependent manner, indicating that Torsins in the perinuclear space can modulate LAP1-chromatin interactions.
Overall, our results reveal new insights into the Torsin-LAP1 interplay, the interaction of LAP1 with nuclear partners and show that a correct balance between Torsin and LAP1 is required to maintain genome integrity.
Link to the paper in external page "eLife".