SCP4 dephosphorylates mitotic histone H3 to maintain chromosome stability.

Mitosis is tightly regulated at multiple levels to ensure chromosome stability. The transient phosphorylation of histone H3 at Threonine 3 (H3T3) during cell division is critical for proper chromosome condensation and the accurate segregation of sister chromatids. While Haspin has been identified as the kinase responsible for H3T3 phosphorylation during mitosis, the phosphatases that counteract this modification to maintain balanced phosphorylation levels remain under investigation. In this study, we systematically screened phosphatases encoded in the human genome and identified the nuclear phosphatase SCP4 as an H3T3 phosphatase. SCP4 modulates H3T3 phosphorylation levels and influences the chromosomal recruitment of chromosomal passenger complex (CPC) during mitosis. Aberrant SCP4 expression leads to defective chromosome separation during metaphase and chromosome lagging in anaphase, resulting in aneuploidy. Notably, in SCP4 knockout mice, zygotes exhibit mitotic defects during the first cleavage at the two-cell stage, highlighting SCP4's essential role in ensuring faithful cell division. In summary, we identify SCP4 as a novel phosphatase regulating H3T3 phosphorylation and chromosome dynamics during mitosis, providing new insights into mechanisms safeguarding genomic stability.