Altered cohesin dynamics and histone H3K9 modifications contribute to mitotic defects in thecbf11Δlipid metabolism mutant

Abstract

Mitotic fidelity is crucial for the faithful distribution of genetic information into the daughter cells. Many fungal species, including the fission yeast Schizosaccharomyces pombe, undergo a closed form of mitosis, during which the nuclear envelope does not break down. In S. pombe numerous processes have been identified that contribute to successful completion of mitosis. Notably, perturbations of lipid metabolism can lead to catastrophic mitosis and the "cut" phenotype. It was suggested that these mitotic defects are caused by insufficient membrane phospholipid supply during the anaphase nuclear expansion. However, it is not clear whether additional factors are involved. In this study we characterized in detail the mitosis in an S. pombe mutant lacking the Cbf11 transcription factor, which regulates lipid metabolism genes. We show that in cbf11Δ cells mitotic defects appear already prior to anaphase, before the nuclear expansion begins. Moreover, we identify altered cohesin dynamics and centromeric chromatin structure as additional factors affecting mitotic fidelity in cells with disrupted lipid homeostasis, providing new insights into this fundamental biological process.

Critical importance of DNA binding for CSL protein functions in fission yeast

“…The Δcbf11 mutant had been found to be sensitive to the microtubule poison thiabendazole (TBZ) in a high-throughput screen (Han et al, 2010). We recently confirmed this observation, and detected aberrant chromatin structure and cohesin occupancy at the centromeres in Δcbf11 cells (Vishwanatha et al, 2023). When we now tested the cbf11DBM-TAP strain, it showed TBZ sensitivity comparable to the Δcbf11 mutant (Fig.…”

“…Cells lacking CSL genes display a wide range of phenotypes, including altered cell cycle progression, lipid metabolism, resistance to stresses or cell adhesion (Kwon et al, 2012;Prevorovský et al, 2009;Převorovský et al, 2015;Převorovský et al, 2016;Vachon et al, 2013;Vishwanatha et al, 2023).…”

“…We recently showed that mutations in cbf11 and several lipid metabolism genes (including cut6) result in widespread changes in chromatin structure and in altered expression of oxidative stress-response genes (Princová et al, 2023;Vishwanatha et al, 2023). Therefore, we tested whether there is a more general link between lipid metabolism and the cellular resistance to genotoxic stress.…”

“…Moreover, we recently identified additional factors contributing to mitotic defects in Δcbf11 cells, such as perturbed structure of centromeric chromatin and aberrant cohesin occupancy (Vishwanatha et al, 2023). However, the molecular details of how dysregulated lipid metabolism leads to these various cell cycle defects remain elusive.…”

Cbf11 and Mga2 function as a single regulatory entity to activate transcription of lipid metabolism genes and promote mitotic fidelity in fission yeast

“…We have recently described a requirement for Cbf11 in the maintenance of chromatin structure and genome integrity. Cells lacking intact Cbf11 are sensitive to the microtubule poison thiabendazole (TBZ), and to camptothecin (CPT), an inhibitor of topoisomerase II and a potent inducer of double-stranded DNA breaks (Marešová et al, 2024; Vishwanatha et al, 2023). We now tested whether Mga2 is also involved in these processes.…”