Lamin B1 Polymorphism Influences Morphology of the Nuclear Envelope, Cell Cycle Progression, and Risk of Neural Tube Defects in Mice

SummaryNucleoporins (Nups) build highly organized Nuclear Pore Complexes (NPCs) at the nuclear envelope (NE). Several Nups assemble into a sieve-like hydrogel within the central channel of the NPCs to regulate nucleocytoplasmic exchange. In the cytoplasm, a large excess of soluble Nups has been reported, but how their assembly is restricted to the NE is currently unknown. Here we show that Fragile X-related protein 1 (FXR1) can interact with several Nups and facilitate their localization to the NE during interphase through a microtubule and dynein-dependent mechanism. Downregulation of FXR1 or closely related orthologs FXR2 and Fragile X mental retardation protein (FMRP) leads to the accumulation of cytoplasmic Nup protein condensates. Likewise, several models of Fragile X syndrome (FXS), characterized by a loss of FMRP, also accumulate cytoplasmic Nup aggregates. These aggregate-containing cells display aberrant nuclear morphology and a delay in G1 cell cycle progression. Our results reveal an unexpected role for the FXR protein family and dynein in the spatial regulation of nucleoporin assembly.HighlightsCytoplasmic nucleoporins are assembled by Fragile X-related (FXR) proteins and dyneinFXR-Dynein pathway downregulation induces aberrant cytoplasmic aggregation of nucleoporinsCellular models of Fragile X syndrome accumulate aberrant cytoplasmic nucleoporin aggregates.FXR-Dynein pathway regulates nuclear morphology and G1 cell cycle progressioneTOC BlurbNucleoporins (Nups) form Nuclear Pore Complexes (NPCs) at the nuclear envelope. Agote-Arán at al. show how cells inhibit aberrant assembly of Nups in the cytoplasm and identify Fragile X-related (FXR) proteins and dynein that facilitate localization of Nups to the nuclear envelope and control G1 cell cycle progression.Graphical abstract

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PROFILING OF Y1 CELLS TREATED WITH FGF-2 REVEALS PARALLELS WITH ONCOGENE-INDUCED SENESCENCE

10.1101/2020.08.17.247023 ◽

2020 ◽

Author(s):

Peder J. Lund ◽

Mariana Lopes ◽

Simone Sidoli ◽

Mariel Coradin ◽

Francisca Nathália de Luna Vitorino ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Proteome Analysis ◽

Tca Cycle ◽

Sequencing Analysis ◽

Histone H4 ◽

Cycle Progression ◽

Lamin B1 ◽

The Tca Cycle ◽

Tgfb Signaling

ABSTRACTParadoxically, oncogenes that drive cell cycle progression may also trigger pathways leading to senescence, thereby inhibiting the growth of tumorigenic cells. Along these lines, Y1 cells, which carry an amplification of Ras, become senescent after treatment with the mitogen FGF-2. To understand how FGF-2 promotes senescence, we profiled the epigenome, transcriptome, proteome, and phospho-proteome of Y1 cells stimulated with FGF-2. FGF-2 caused delayed acetylation of histone H4 and higher levels of H3K27me3. Sequencing analysis revealed decreased expression of cell cycle-related genes with concomitant loss of H3K27ac. In contrast, FGF-2 promoted the expression of p21, various cytokines, and MAPK-related genes. Nuclear envelope proteins, particularly lamin B1, displayed increased phosphorylation in response to FGF-2. Proteome analysis suggested alterations in cellular metabolism, as evident by modulated expression of enzymes involved in purine biosynthesis, tRNA aminoacylation, and the TCA cycle. Altogether, the response of Y1 cells to FGF-2 is consistent with oncogene-induced senescence. We propose that Y1 cells enter senescence due to deficient cyclin expression and high levels of p21, which may stem from DNA damage or TGFb signaling.

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LAP1 is a crucial protein for the maintenance of the nuclear envelope structure and cell cycle progression

Molecular and Cellular Biochemistry ◽

10.1007/s11010-014-2241-x ◽

2014 ◽

Vol 399 (1-2) ◽

pp. 143-153 ◽

Cited By ~ 17

Author(s):

Mariana Santos ◽

Patrícia Costa ◽

Filipa Martins ◽

Edgar F. da Cruz e Silva ◽

Odete A. B. da Cruz e Silva ◽

...

Keyword(s):

Cell Cycle ◽

Nuclear Envelope ◽

Cell Cycle Progression ◽

Cycle Progression

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Phactr4 Regulates Neural Tube and Optic Fissure Closure by Controlling PP1-, Rb-, and E2F1-Regulated Cell-Cycle Progression

Developmental Cell ◽

10.1016/j.devcel.2007.04.018 ◽

2007 ◽

Vol 13 (1) ◽

pp. 87-102 ◽

Cited By ~ 69

Author(s):

Tae-Hee Kim ◽

Jessica Goodman ◽

Kathryn V. Anderson ◽

Lee Niswander

Keyword(s):

Cell Cycle ◽

Neural Tube ◽

Cell Cycle Progression ◽

Cycle Progression

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Centripetal nuclear shape fluctuations associate with chromatin condensation towards mitosis

10.1101/2021.11.25.469847 ◽

2021 ◽

Author(s):

Viola Introini ◽

Gururaj Rao Kidiyoor ◽

Giancarlo Porcella ◽

Marco Foiani ◽

Pietro Cicuta ◽

...

Keyword(s):

Cell Cycle ◽

Nuclear Envelope ◽

Cell Cycle Progression ◽

Chromatin Condensation ◽

Nuclear Shape ◽

Cycle Progression ◽

Cellular Processes ◽

Nuclear Envelope Breakdown ◽

Nuclear Mechanics ◽

Nuclear Processes

The cell nucleus plays a central role in several key cellular processes, including chromosome organisation, replication and transcription. Recent work intriguingly suggests an association between nuclear mechanics and cell-cycle progression, but many aspects of this connection remain unexplored. Here, by monitoring nuclear shape fluctuations at different cell cycle stages, we uncover increasing inward fluctuations in late G2 and early mitosis, which are initially transient, but develop into instabilities that culminate into nuclear-envelope breakdown in mitosis. Perturbation experiments and correlation analysis reveal an association of these processes with chromatin condensation. We propose that the contrasting forces between an extensile stress and centripetal pulling from chromatin condensation could link mechanically chromosome condensation and nuclear-envelope breakdown, the two main nuclear processes during mitosis.

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Nuclear envelope influences on cell-cycle progression

Biochemical Society Transactions ◽

10.1042/bst20110656 ◽

2011 ◽

Vol 39 (6) ◽

pp. 1742-1746 ◽

Cited By ~ 6

Author(s):

Vlastimil Srsen ◽

Nadia Korfali ◽

Eric C. Schirmer

Keyword(s):

Cell Cycle ◽

Nuclear Envelope ◽

Cell Cycle Progression ◽

Membrane System ◽

Regulatory Proteins ◽

Cycle Progression ◽

Cytoplasmic Surface ◽

Dynamic Interface ◽

Gene Regulatory ◽

Cycle Regulation

The nuclear envelope is a complex double membrane system that serves as a dynamic interface between the nuclear and cytoplasmic compartments. Among its many roles is to provide an anchor for gene regulatory proteins on its nucleoplasmic surface and for the cytoskeleton on its cytoplasmic surface. Both sets of anchors are proteins called NETs (nuclear envelope transmembrane proteins), embedded respectively in the inner or outer nuclear membranes. Several lines of evidence indicate that the nuclear envelope contributes to cell-cycle regulation. These contributions come from both inner and outer nuclear membrane NETs and appear to operate through several distinct mechanisms ranging from sequestration of gene-regulatory proteins to activating kinase cascades.

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