Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 100, Issue 6, Pages 3095-3100Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0538069100
Keywords
ACC1; VLCF; very long-chain fatty acid
Categories
Funding
- NIGMS NIH HHS [GM 63115, F32 GM019091, R01 GM063115, GM 19091] Funding Source: Medline
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To elucidate the essential functions of acetyl-CoA carboxylase (ACC1/FAS3) in Saccharomyces cerevisiae, a temperature-sensitive mutant (acc1(ts)) was constructed. When the acc1(ts) cells were synchronized in G(1) phase with alpha-factor at the permissive temperature of 24degreesC and then released from the blockade and incubated at the restrictive temperature of 37degreesC, 95% of the cell population became arrested at the G(2)/M phase of the cell cycle despite the presence of fatty acids (C-14-C-26) in the medium. These cells developed large undivided nuclei, and the spindles of the arrested mutant cells were short. Shifting the G(2) arrested cells back to the permissive temperature resulted in a reversal of the cell-cycle arrest, with cells initiating mitosis. However, after 3 h of incubation at 37degreesC, G(2) arrested mutant cells lost viability and displayed a uniquely altered nuclear envelope. Using [1-C-14]acetate as a precursor for fatty acids synthesis, we identified the phospholipids and sphingolipids derived from acc1(ts) cells and wild-type cells at 24degreesC and 37degreesC, respectively. The levels of inositol-ceramides [IPC, MIPC, and M(IP)(2)C] and very long-chain fatty acids C-24 and C-26 declined sharply in the G(2)/M arrested cells because of ACC inactivation. Shifting the acc1(ts) cells to 24degreesC after 2 h of incubation at 37degreesC resulted in reactivation of the ACC and elevation of the ceramides and very long-chain fatty acid syntheses with normal cell-cycle progression. In contrast, synthesis of wild-type inositol-cera m ides, C-24 and C-26, fatty acids were elevated on incubation at 37degreesC and declined when the cells shifted to the permissive temperature of 24degreesC.
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