A fast-acting lipid checkpoint in G1 prevents mitotic defects
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PROVIDER: PRJNA1070642 | ENA |
REPOSITORIES: ENA
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Project description:Lipid synthesis must increase during the cell cycle to double 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 in non-transformed cells. 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 failure and cell death, which are triggered by low lipid synthesis much later in mitosis.
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Project description:<p>Characterizing the mode of action of antimalarial compounds that emerge from high-throughput phenotypic screens is central to understanding how parasite resistance to these drugs can emerge. Here, we have employed untargeted metabolomics to inform on the mechanism of action of antimalarial leads with different speed of kill profiles being developed by the Novartis Institute of Tropical Diseases (NITD). Time-resolved global changes in malaria parasite metabolite profiles upon drug treatment were quantified using liquid chromatography-based mass spectrometry (LC-MS) and compared to untreated controls. Using this approach, we confirmed previously reported metabolomics profiles of the fast-killing (2.5 h) drug dihydroartemisinin (DHA) and the slower killing atovaquone (ATQ). A slow acting antimalarial lead from NITD of imidazolopiperazine (IZP) class, GNF179, elicited little or no discernable metabolic change in malaria parasites in the same 2.5 h window of drug exposure. In contrast, fast killing drugs, DHA and the spiroindolone (NITD246) elicited similar metabolomic profiles both in terms of kinetics and content. DHA and NITD246 induced peptide losses consistent with disruption of haemoglobin catabolism and also interfered with the pyrimidine biosynthesis pathway. Two members of the recently described novel class of antimalarial agents of the 5-aryl-2-amino-imidazothiadiazole (ITD) class also exhibited a fast-acting profile that also featured peptide losses indicative of disrupted haemoglobin catabolism. Our screen demonstrates that structurally unrelated, fast acting antimalarial compounds generate similar biochemical signatures in <em>Plasmodium</em> pointing to a common mechanism associated with rapid parasite death. These profiles may be used to identify and possibly predict the mode of action of other fast-acting drug candidates.</p>
2023-09-27 | MTBLS6580 | MetaboLights
Project description:HeLa mitotic cells were collected using a mitotic shakeoff apparatus to study gene expression in early G1 phase of the human cell cycle. This set includes microarray data from two shake-off experiments : shake 1 (0h-14h) which was conducted over 14 hours and RNA samples collected every 2 hrs, and shake 2 (0min-120min) which was conducted over 2 hours and samples collected every 15 minutes. Total RNA was prepared using ULTRASPEC RNA isolation system, and Reference RNA was extracted from asynchronously growing HeLa cells using TRIzol. For cDNA synthesis and microarray hybridization, refer to Whitfield ML. et al., Mol Biol Cell, 2002. 13(6): p. 1977-2000. Groups of assays that are related as part of a time series. Age: g1 progression after mitotic shake-off Replicate: two biological replicates (shake1 and shake2) Keywords: time_series_design Computed
2010-06-25 | E-GEOD-12473 | biostudies-arrayexpress
Project description:HeLa mitotic cells were collected using a mitotic shakeoff apparatus to study gene expression in early G1 phase of the human cell cycle. This set includes microarray data from two shake-off experiments : shake 1 (0h-14h) which was conducted over 14 hours and RNA samples collected every 2 hrs, and shake 2 (0min-120min) which was conducted over 2 hours and samples collected every 15 minutes. Total RNA was prepared using ULTRASPEC RNA isolation system, and Reference RNA was extracted from asynchronously growing HeLa cells using TRIzol. For cDNA synthesis and microarray hybridization, refer to Whitfield ML. et al., Mol Biol Cell, 2002. 13(6): p. 1977-2000. Groups of assays that are related as part of a time series. Age: g1 progression after mitotic shake-off Replicate: two biological replicates (shake1 and shake2) Keywords: time_series_design
2009-02-26 | GSE12473 | GEO
Project description:The prevailing dogma is that renewed mitogenic signaling is essential to traverse G1 phase of the cell cycle after each division. B lymphocytes undergo multiple mitotic divisions, termed clonal expansion, to expand antigen-specific cells that mediate effective immunity. We explored mechanisms by which primary murine B lymphocytes make cell division decisions. We demonstrate that commitment to DNA replication _S phase_ programs B cells to divide multiple times in the absence of overt mitogenic signaling. The extent of division is limited by cell death rather than by return to quiescence, and circumventing cell death permits up to 4 rounds of division in 72h. Mitogen-independent cell cycle progression is driven by unique S- and G2/M- like characteristics of the G1 phase of cells that have divided once, such as, large cell size, low levels of p27, phosphorylated Rb and expression of G2/M markers survivin, Cenp-A and Aim1/Aurora B. Pharmacologic inhibition of survivin blocked G1 progression in a B cell line and in primary B cells undergoing mitogen-independent division. These observations indicate that, in contrast to textbook models of the cell cycle, B cells inherit a partially active G1 phase after cell division that permits them to move quickly to the next S phase in the absence of exogenous G1 progression signals. Our studies provide direct evidence for Pardee’s hypothesis that retention of features of G2/M in post-mitotic cells could trigger a second round of cell cycle progression. We propose that these mechanisms may assist in rapid cell division without differentiation that is required for clonal expansion in response to antigens.
2022-04-29 | GSE195698 | GEO
Project description:We provide the genome-wide map of Esrrb binding in mitotic and asynchronous ES cells together with the Esrrb-induced transcriptomic changes in early G1, late G1 and G2.
2016-08-29 | GSE75066 | GEO
Project description:Non mitotic tumor cells are resistant to conventional chemotherapeutic drugs. However, the mechanisms underlying this phenomenon remain unclear. Here, we found a population that is viable but remains in the G1 phase for an extended period of time (up to 48 h) by Long-term time-lapse observations in Fucci-HCT116 cells and then we conducted DNA microarray-based comparative analyses between the RR (the long-term G1-arrested cells) and R (the G1-arrested cells) fractions, to determine the molecular basis of the G1 arrest/maintenance mechanism. This study is related to GSE34940.
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Project description:By following chromatin occupancy of RNAPII and TOP1 using ChIP-seq throughout mitosis, we found that TOP1 is required for RNAPII translocation along genes. The stimulation of TOP1 activity through its interaction with RNAPII during elongation, allowed RNAPII clearance from genes in prometaphase and enabled proper chromosomal segregation. Interference with the TOP1-RNAPII interaction or acute depletion of TOP1 at the onset of mitosis impaired RNAPII spiking at promoters, which is necessary for the first pioneering round of transcription during mitotic exit, and triggered defects in the transcriptional program of the post-mitotic cells.
2021-11-11 | GSE171132 | GEO