Altered cohesin dynamics and 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.

Nitrogen availability and TOR signalling are important for preventing catastrophic mitosis in fission yeast

“…2). These results are consistent with our recent findings that, in addition to any issues with the production of new membranes, mitotic fidelity in lipid metabolism mutants is affected by changes in centromeric chromatin structure and cohesin dynamics [18]. While we did not detect any nitrogen-dependent improvement in mitotic NE dynamics and FA and lipid composition composition, we found that ammonium supplementation clearly normalised the timing of mitotic progression, restoring the duration of individual mitotic phases close to their WT state (Fig.…”

“…Indeed, we previously showed that ammonium supplementation did not correct the aberrant lipid droplet (LD) content of Δcbf11 cells [26]. Also, we demonstrated that the defects in Δcbf11 mitosis manifest already before anaphase [18].…”

“…For each sample at least ten images (~500-1500 cells total) were acquired. Frequency of catastrophic mitosis was counted manually using our standard scoring criteria [18].…”

“…It was assumed that decreased supply of precursors of membrane phospholipids (PL) leads to insufficient NE expansion during anaphase and mitotic failure [17]. However, we recently found additional factors contributing to decreased mitotic fidelity in cells with perturbed lipid metabolism, as cbf11 and cut6 mutants show altered cohesin dynamics and H3K9 modifications at the centromeric regions [18].…”

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.…”