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Published on: June 6, 2017
Cell cycle regulation of ER membrane biogenesis protects against chromosome missegregation
Holly Merta1, Jake W Carrasquillo Rodríguez1, Maya I Anjur-Dietrich2
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA.
Abstract:
Failure to reorganize the endoplasmic reticulum (ER) in mitosis results in chromosome missegregation. Here, we show that accurate chromosome segregation in human cells requires cell cycle-regulated ER membrane production. Excess ER membranes increase the viscosity of the mitotic cytoplasm to physically restrict chromosome movements, which impedes the correction of mitotic errors leading to the formation of micronuclei. Mechanistically, we demonstrate that the protein phosphatase CTDNEP1 counteracts mTOR kinase to establish a dephosphorylated pool of the phosphatidic acid phosphatase lipin 1 in interphase. CTDNEP1 control of lipin 1 limits the synthesis of fatty acids for ER membrane biogenesis in interphase that then protects against chromosome missegregation in mitosis. Thus, regulation of ER size can dictate the biophysical properties of mitotic cells, providing an explanation for why ER reorganization is necessary for mitotic fidelity. Our data further suggest that dysregulated lipid metabolism is a potential source of aneuploidy in cancer cells.
Insights
Accurate cell division requires controlling endoplasmic reticulum (ER) size. Proper ER membrane production prevents errors in chromosome segregation, reducing micronuclei formation and supporting mitotic fidelity.
Area of Science:
- Cell Biology
- Molecular Biology
- Biophysics
Background:
- Endoplasmic reticulum (ER) reorganization is crucial for accurate chromosome segregation during mitosis.
- Failure to manage ER structure can lead to mitotic errors and aneuploidy.
Purpose of the Study:
- To investigate the role of cell cycle-regulated ER membrane production in maintaining mitotic fidelity.
- To elucidate the molecular mechanisms controlling ER biogenesis and its impact on chromosome segregation.
Main Methods:
- Utilized human cell lines.
- Investigated protein phosphatase CTDNEP1, mTOR kinase, and lipin 1 pathways.
- Analyzed ER membrane biogenesis and its effect on cytoplasmic viscosity and chromosome movement during mitosis.
Main Results:
- Cell cycle-regulated ER membrane production is essential for accurate chromosome segregation.
- Excess ER membranes increase cytoplasmic viscosity, hindering error correction and promoting micronuclei formation.
- CTDNEP1 counteracts mTOR to limit interphase ER membrane synthesis, thereby preventing mitotic errors.
Conclusions:
- Regulation of ER size is a key determinant of mitotic cell biophysics and fidelity.
- Dysregulated lipid metabolism and ER biogenesis contribute to aneuploidy, potentially in cancer cells.
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