SETD1A protects from senescence through regulation of the mitotic gene expression program

SETD1A, a member of the Set1/COMPASS family maintaining H3K4 methylation in the promoters of transcriptionally active genes, is critical for the execution of developmental gene expression and is overexpressed in multiple cancers including breast cancer1-3. Here we show that SETD1A is essential for supporting cellular mitotic processes and consequentially, its depletion leads to senescence. SETD1A directly regulates the expression of several genes orchestrating mitosis and DNA damage responses and its depletion results in multiple mitotic defects including chromosome misalignment and segregation defects. Senescence-associated cell cycle arrest in SETD1A knockdown cells is independent of the mutational status of p53, RB and p16, key mediators of this process, instead, is sustained through direct transcriptional suppression of SKP2, the ubiquitin ligase, which degrades p27 and p21. Rare cells escape senescence and re-enter the cell cycle by restoring SKP2 expression but with enhanced genomic instability. In >200 cancer cell lines and in primary circulating tumor cells, expression of SETD1A correlates with genes involved in mitosis and cell cycle suggesting a role in suppressing senescence induced by aberrant mitosis. Thus, SETD1A encodes a chromatin modifier, whose modulation may maintain the balance between senescence and genomic instability in cells. Compare histon H3K4 trimethylation status between groups