Collectively, our findings demonstrate that H2Bub1 removal in early mitosis is critical for higher-order chromatin compaction, accurate chromosome segregation and the maintenance of chromosome stability, and they further identify USP22 as a novel CIN gene, consistent with diminished USP22 expression being a pathogenic event contributing to oncogenesis. Here, USP22 is linked to cervical squamous intraepithelial neoplasia.