Acetyl-CoA Carboxylase Alpha the Rate-limiting Enzyme of Fatty Acid Synthesis Modulates Mitotic Progression and Chromosome Segregation

  • Jorge Landgrave-Gomez

Student thesis: Doctoral Thesis

Abstract

While metabolic enzymes inside the cell nucleus were initially considered “contaminants”, recent evidence has shown that these fulfill essential functions in epigenetic regulation. Indeed a model is emerging in which local metabolite pools influence various nuclear processes. In this model, the subcellular distribution and organization of metabolic factors have a crucial role in the complex logic and regulation of nuclear functions. Cancer cells exploit nuclear metabolic enzymes to alter the synthesis and utilization of metabolites that sustain their transcriptional programs allowing their abnormal proliferation. Understanding the precise molecular mechanisms that modulate the distribution of nuclear metabolic enzymes and their related biological functions has the potential to uncover novel therapeutic vulnerabilities of malignant cells. Here, we describe an unexpected subcellular distribution of acetyl-CoA carboxylase alpha (ACC1), the rate-limiting enzyme of de novo fatty acid synthesis. We found that in cancer cells, ACC1 is not restricted to the cytoplasm. Instead, at mitosis and after the nuclear envelope breakdown, it transiently redistributes into filament-like structures that contact condensed chromosomes. Simultaneous profiling of protein-protein and -DNA interactions defined ACC1 association with different factors associated with the cellular machinery that modulates chromosome segregation, including the centromere, the kinetochore, and the fibrous corona. Inducible depletion of ACC1 resulted in altered mitotic progression and accumulation of chromosome segregation defects – effects that are abolished only with the reconstituted expression of catalytically active mutants of ACC1 but not its inactive counterparts. We further found that the abundance of malonyl-CoA – the main product of ACC1 enzymatic activity – gradually increases towards the onset of mitosis, being a significant determinant for histone malonylation. Overall we uncovered a previously unknown function of ACC1 in modulating mitotic progression and chromosome segregation. Our findings support a model where local niches of malonyl-CoA might act as signal molecules for faithful chromosome segregation.
Date of AwardOct 2022
Original languageEnglish (US)
Awarding Institution
  • Biological, Environmental Science and Engineering
SupervisorWolfgang Fischle (Supervisor)

Keywords

  • Epigenetics
  • Cellular metabolism
  • Cell cycle
  • Mitosis
  • Chromosome segregation
  • ACC1
  • Malonyl-CoA
  • Lipids

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