Abstract
The nuclear lamina is a filamentous structure subtending the nuclear envelope and required for chromatin organization, transcriptional regulation and maintaining nuclear structure. The trypanosomatid coiled-coil NUP-1 protein is a lamina component functionally analogous to lamins, the major lamina proteins of metazoa. There is little evidence for shared ancestry, suggesting the presence of a distinct lamina system in trypanosomes. To find additional trypanosomatid lamina components we identified NUP-1 interacting proteins by affinity capture and mass-spectrometry. Multiple components of the nuclear pore complex (NPC) and a second coiled-coil protein, which we termed NUP-2, were found. NUP-2 has a punctate distribution at the nuclear periphery throughout the cell cycle and is in close proximity to NUP-1, the NPCs and telomeric chromosomal regions. RNAi-mediated silencing of NUP-2 leads to severe proliferation defects, gross alterations to nuclear structure, chromosomal organization and nuclear envelope architecture. Further, transcription is altered at telomere-proximal variant surface glycoprotein (VSG) expression sites (ESs), suggesting a role in controlling ES expression, although NUP-2 silencing does not increase VSG switching. Transcriptome analysis suggests specific alterations to Pol I-dependent transcription. NUP-1 is mislocalized in NUP-2 knockdown cells and vice versa, implying that NUP-1 and NUP-2 form a co-dependent network and identifying NUP-2 as a second trypanosomatid nuclear lamina component.
Highlights
In metazoan cells the structural organization of the nucleus is maintained, at least in part, by the nuclear lamina, a stable protein meshwork at the inner face of the nuclear envelope (NE), comprised of a small family of coiled-coil intermediate filament lamins [1]
A nuclear lamina is a major feature of most eukaryotic cells, and in metazoan cells is intimately involved in regulating multiple nuclear events
By affinity isolation we identified at least one new lamina component, NUP-2, through its association with NUP-1
Summary
In metazoan cells the structural organization of the nucleus is maintained, at least in part, by the nuclear lamina, a stable protein meshwork at the inner face of the nuclear envelope (NE), comprised of a small family of coiled-coil intermediate filament lamins [1]. Lamins are required for nuclear pore complex (NPC) positioning, with defects leading to NPC clustering [3,4] and/or the absence of NPCs from nuclear blebs [2,5,6]. DNA replication is abolished at the initiation and elongation phases when the lamin network is disrupted [12,13], while lamin mutations lead to increased DNA damage [14]. For these and other reasons, hereditary mutations in lamin genes that cause laminopathies [1,5] are of significant clinical interest
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