Cell cycle regulation of ER membrane biogenesis protects against chromosome missegregation

Merta, Holly; Rodríguez, Jake W. Carrasquillo; Anjur-Dietrich, Maya; Vitale, Tevis; Granade, Mitchell E.; Harris, Thurl E.; Needleman, Daniel; Bahmanyar, Shirin

doi:10.1016/j.devcel.2021.11.009

Cited by 39 publications

(66 citation statements)

References 86 publications

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“…Our 3D EM images of ensheathed chromosomes show that microtubules face a difficult task to negotiate several layers of endomembranes to make the contact between kinetochore and spindle that is necessary for rescue and alignment. In cases where contact is made, endomembranes are also likely to impair the congression of the chromosome, as suggested by a recent study in which excess ER was shown to slow chromosome motions ( Merta et al, 2021 ). Since endomembranes are a risk factor for missegregation, their precise organization—for example the sheet-to-tubule ratio of the ER—may influence the likelihood for missegregation ( Champion et al, 2017 ).…”

Section: Discussionmentioning

confidence: 98%

“…This arrangement means that, although mitosis is open in mammalian cells, the spindle operates within a partially closed system. Several lines of evidence suggest that endomembranes must be cleared from the exclusion zone for the mitotic spindle to function normally ( Vedrenne et al, 2005 ; Schlaitz et al, 2013 ; Champion et al, 2019 ; Kumar et al, 2019 ; Merta et al, 2021 ). In addition, it is thought that this arrangement is required to concentrate factors needed for spindle formation ( Schweizer et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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Endomembranes promote chromosome missegregation by ensheathing misaligned chromosomes

Ferrándiz

Downie

Starling

et al. 2022

Journal of Cell Biology

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Errors in mitosis that cause chromosome missegregation lead to aneuploidy and micronucleus formation, which are associated with cancer. Accurate segregation requires the alignment of all chromosomes by the mitotic spindle at the metaphase plate, and any misalignment must be corrected before anaphase is triggered. The spindle is situated in a membrane-free “exclusion zone”; beyond this zone, endomembranes (mainly endoplasmic reticulum) are densely packed. We investigated what happens to misaligned chromosomes localized beyond the exclusion zone. Here we show that such chromosomes become ensheathed in multiple layers of endomembranes. Chromosome ensheathing delays mitosis and increases the frequency of chromosome missegregation and micronucleus formation. We use an induced organelle relocalization strategy in live cells to show that clearance of endomembranes allows for the rescue of chromosomes that were destined for missegregation. Our findings indicate that endomembranes promote the missegregation of misaligned chromosomes that are outside the exclusion zone and therefore constitute a risk factor for aneuploidy.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Endomembranes promote chromosome missegregation by ensheathing misaligned chromosomes

Ferrándiz

Downie

Starling

et al. 2022

Journal of Cell Biology

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“…Lipid synthesis is a universal mechanism that controls nuclear size and shape ( Barger et al, 2022 ; Grillet et al, 2016 ; Kume et al, 2017 ; Merta et al, 2021 ; Santos-Rosa et al, 2005 ), and future work is needed to understand the direct and indirect relationships between ER/NE membrane biogenesis, NPC assembly pathways, and nuclear transport rates to regulate NPC density, nuclear expansion, and nuclear size.…”

Section: Discussionmentioning

confidence: 99%

Ndc1 drives nuclear pore complex assembly independent of membrane biogenesis to promote nuclear formation and growth

Mauro

Celma

Zimyanin

et al. 2022

eLife

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The nuclear envelope (NE) assembles and grows from bilayer lipids produced at the endoplasmic reticulum (ER). How ER membrane incorporation coordinates with assembly of nuclear pore complexes (NPCs) to generate a functional NE is not well understood. Here, we use the stereotypical first division of the early C. elegans embryo to test the role of the membrane-associated nucleoporin Ndc1 in coupling NPC assembly to NE formation and growth. 3D-EM tomography of reforming and expanded NEs establishes that Ndc1 determines NPC density. Loss of ndc1 results in faster turnover of the outer scaffold nucleoporin Nup160 at the NE, providing an explanation for how Ndc1 controls NPC number. NE formation fails in the absence of both Ndc1 and the inner ring component Nup53, suggesting partially redundant roles in NPC assembly. Importantly, upregulation of membrane synthesis restored the slow rate of nuclear growth resulting from loss of ndc1 but not from loss of nup53. Thus, membrane biogenesis can be decoupled from Ndc1-mediated NPC assembly to promote nuclear growth. Together, our data suggest that Ndc1 functions in parallel with Nup53 and membrane biogenesis to control NPC density and nuclear size.

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“…It was indeed recently observed that the ER organization was disrupted in hepatocytes from obese mice, due to an imbalance between the levels of CLIMP-63 and ER tubuleassociated proteins, which could be rescued by the exogenous overexpression of CLIMP-63 50 . Another recent study found that excess fatty acid synthesis leads to the densi cation of ER membranes causing downstream mitotic complications 51 . A link between lipid metabolism and protein acylation, although expected, remains to be explored and mechanistically understood.…”

Section: Discussionmentioning

confidence: 99%

Model-driven understanding of CLIMP-63 structure and S-acylation reveals fine tuning of ER morphology

Sandoz

Denhardt-Eriksson

Abrami

et al. 2022

Preprint

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The complex architecture of the endoplasmic reticulum (ER) comprises distinct dynamic features, many at the nanoscale, that enable the coexistence of the nuclear envelope, regions of dense sheets and a branched tubular network that spans the cytoplasm. A key player in the formation of ER sheets is cytoskeleton-linking membrane protein 63 (CLIMP-63). The mechanisms by which CLIMP-63 coordinates ER structure remain elusive. Here, we addressed the impact of S-acylation, a reversible post-translational lipid modification, on CLIMP-63 cellular distribution and function. Combining native mass-spectrometry, with kinetic analysis of acylation and deacylation, and data-driven mathematical modelling, we obtained in depth understanding of the CLIMP-63 life-cycle. In the ER, it assembles into trimeric units. These occasionally exit the ER to reach the plasma membrane. However, the majority undergoes S-acylation by ZDHHC6 in the ER where they further assemble into highly stable super-complexes. Using super resolution microscopy and focused ion beam electron microscopy, we show that CLIMP-63 acylation-deacylation controls the abundance and fenestration of ER sheets. Overall, this study led to the discovery that dynamic lipid post-translational modifications can regulate ER architecture.

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Cell cycle regulation of ER membrane biogenesis protects against chromosome missegregation

Cited by 39 publications

References 86 publications

Endomembranes promote chromosome missegregation by ensheathing misaligned chromosomes

Endomembranes promote chromosome missegregation by ensheathing misaligned chromosomes

Ndc1 drives nuclear pore complex assembly independent of membrane biogenesis to promote nuclear formation and growth

Model-driven understanding of CLIMP-63 structure and S-acylation reveals fine tuning of ER morphology

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