2. Academic Validation
  3. A fast-acting lipid checkpoint in G1 prevents mitotic defects

A fast-acting lipid checkpoint in G1 prevents mitotic defects

  • Nat Commun. 2024 Mar 18;15(1):2441. doi: 10.1038/s41467-024-46696-9.
Marielle S Köberlin 1 2,  Yilin Fan 3 4,  Chad Liu 3 5,  Mingyu Chung 3 6,  Antonio F M Pinto 7,  Peter K Jackson 8 9,  Alan Saghatelian 7,  Tobias Meyer 10 11
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA. mkoeberlin@stanford.edu.
  • 2 Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. mkoeberlin@stanford.edu.
  • 3 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 4 Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
  • 5 Chan Zuckerberg Biohub, San Francisco, CA, 94111, USA.
  • 6 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 7 Clayton Foundation Laboratories for Peptide Biology and Mass Spectrometry Core, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
  • 8 Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 9 Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 10 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA. tom4003@med.cornell.edu.
  • 11 Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, 10065, USA. tom4003@med.cornell.edu.
PMID: 38499565 DOI: 10.1038/s41467-024-46696-9
Abstract

Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated Phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.

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