SOX2 phosphorylation during mitosis limits genomic damage [ChIP-Seq 2]

Pioneer transcription factors (TFs) such as SOX2 play critical roles in control of stem cell identity and are dysregulated in many human cancers. For example, SOX2 regulates the self-renewal of neural stem cells (NSCs), and is typically highly expressed in glioblastoma stem cells, where it is known to induce an immature NSC-like state. Here, we explored the regulation of SOX2 by phosphorylation during cell division and identify an unexpected role for mitotic SOX2 as an inducer of genomic damage. We find that SOX2 adopts a distinct phosphorylated state in NSCs during mitosis, regulated by the mitotic kinase CDK1. Mapping of SOX2 genome occupancy and chromatin accessibility shows that a subset of SOX2 remains bound to the interphase targets, consistent with mitotic bookmarking, but phosphorylated SOX2 is redistributed to constitutive heterochromatin, including telomeres. Ablation of SOX2 phosphorylation leads to promiscuous chromatin binding across the genome and triggers prolonged mitotic transit times and increased susceptibility to DNA damage. These findings show that excessive levels of SOX2 protein in mitosis trigger inappropriate opening of chromatin and downstream chromosomal damage. Elevated levels of SOX2 in cancers may therefore have dual oncogenic roles: imposing stemness during interphase via their well-known transcriptional roles, but simultaneously inducing genomic damage during mitosis due to their unconstrained pioneer factor activity.