Histone stress: an unexplored source of chromosomal instability in cancer?

Ploidy is stably maintained in most human somatic cells by a sequential and tight coordination of cell cycle events. Undesired whole genome doublings or duplications are frequent in tumours and have been quite recently described as macro-evolutionary events associated with poor prognosis. In vitro and in vivo studies suggest that polyploidy can favour genome instability, facilitate the formation and progression of tumours, and modify their sensitivity to chemotherapeutic agents. Stress is strongly related to changes in ploidy and whole genome doublings. In this review, we summarize different mechanisms that promote polyploidization, describe a new type of stress able to trigger WGDs in S. cerevisiae, histone stress, and provide some examples and theoretical scenarios that support that cancer cells might suffer from this type of stress. We finally highlight some results showing that the kinase Swe1 (Wee1 in humans) has a role in sensing histone levels before cells enter mitosis, thereby avoiding their undesired consequences on chromosome segregation and ploidy control.

Coordination of Cell Cycle Progression and Mitotic Spindle Assembly Involves Histone H3 Lysine 4 Methylation by Set1/COMPASS.

Methylation of histone H3 lysine 4 (H3K4) by Set1 complex/COMPASS is a hallmark of eukaryotic chromatin, but it remains poorly understood how this post-translational modification contributes to the regulation of biological processes like the cell cycle. Here, we report a H3K4 methylation-dependent pathway in Saccharomyces cerevisiae that governs toxicity toward benomyl, a microtubule destabilizing drug. Benomyl-sensitive growth of wild-type cells required mono- and dimethylation of H3K4 and Pho23, a PHD-containing subunit of the Rpd3L complex. Δset1 and Δpho23 deletions suppressed defects associated with ipl1-2 aurora kinase mutant, an integral component of the spindle assembly checkpoint during mitosis. Benomyl resistance of Δset1 strains was accompanied by deregulation of all four tubulin genes and the phenotype was suppressed by tub2-423 and Δtub3 mutations, establishing a genetic link between H3K4 methylation and microtubule function. Most interestingly, sine wave fitting and clustering of transcript abundance time series in synchronized cells revealed a requirement for Set1 for proper cell-cycle-dependent gene expression and Δset1 cells displayed delayed entry into S phase. Disruption of G1/S regulation in Δmbp1 and Δswi4 transcription factor mutants duplicated both benomyl resistance and suppression of ipl1-2 as was observed with Δset1 Taken together our results support a role for H3K4 methylation in the coordination of cell-cycle progression and proper assembly of the mitotic spindle during mitosis.