Abstract
The inner nuclear membrane is functionalized by diverse transmembrane proteins that associate with nuclear lamins and/or chromatin. When cells enter mitosis, membrane-chromatin contacts must be broken to allow for proper chromosome segregation; yet how this occurs remains ill-understood. Unexpectedly, we observed that an imbalance in the levels of the lamina-associated polypeptide 1 (LAP1), an activator of ER-resident Torsin AAA+-ATPases, causes a failure in membrane removal from mitotic chromatin, accompanied by chromosome segregation errors and changes in post-mitotic nuclear morphology. These defects are dependent on a hitherto unknown chromatin-binding region of LAP1 that we have delineated. LAP1-induced NE abnormalities are efficiently suppressed by expression of wild-type but not ATPase-deficient Torsins. Furthermore, a dominant-negative Torsin induces chromosome segregation defects in a LAP1-dependent manner. These results indicate that association of LAP1 with chromatin in the nucleus can be modulated by Torsins in the perinuclear space, shedding new light on the LAP1-Torsin interplay.
Highlights
In all eukaryotes, a double membrane barrier termed nuclear envelope (NE) serves as the boundary of the nuclear compartment that safeguards the genetic information
We tested whether it is possible to impair the release of the NE membranes from mitotic chromatin if any cellular factor involved in dissolving inner nuclear membrane (INM) protein-chromatin contacts would become limiting by a disturbed ratio between INM proteins and the potential release factor(s)
The LAP1induced NE aberrations were observed in the vast majority of cells when analyzed after 48 hr, whereas most cells still displayed a normal nuclear morphology after 24 hr, perhaps because more cells had progressed through mitosis in presence of lamina-associated polypeptide 1 (LAP1) at the later time point
Summary
A double membrane barrier termed nuclear envelope (NE) serves as the boundary of the nuclear compartment that safeguards the genetic information. Enrichment of these membrane proteins from the peripheral ER at the nuclear face of the NE relies on several domains or short linear motifs in their extralumenal domains that together ensure retention on nuclear partners such as nuclear lamins, chromatin-associated factors or DNA (Boni et al, 2015; Powell and Burke, 1990; Ungricht et al, 2015a). While the interaction of INM proteins with the nuclear lamina is restricted to lamin-expressing metazoan cells and certain protists, chromatin is the principal binding partner of INM proteins in all eukaryotes. The association of INM proteins with chromatin is functionally important, being it for the formation of gametes, for development or differentiation, exemplified by the NE-based pairing of homologous chromosomes during meiosis, or the progressive enrichment of transcriptionally repressed chromatin domains at the nuclear periphery of differentiating metazoan cells (Ungricht and Kutay, 2017)
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