HIPK2 Controls Cytokinesis and Prevents Tetraploidization by Phosphorylating Histone H2B at the Midbody

• Published in: Molecular cell 2012-07, Vol.47 (1), p.87-98
• Main Authors: Rinaldo, Cinzia, Moncada, Alice, Gradi, Alessandra, Ciuffini, Laura, D'Eliseo, Donatella, Siepi, Francesca, Prodosmo, Andrea, Giorgi, Alessandra, Pierantoni, Giovanna M., Trapasso, Francesco, Guarguaglini, Giulia, Bartolazzi, Armando, Cundari, Enrico, Schininà, M. Eugenia, Fusco, Alfredo, Soddu, Silvia
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Carrier Proteins - genetics; Carrier Proteins - metabolism; cell cleavage; Cell Division; Cell Line; Cell Line, Tumor; cell proliferation; cells; Cytokinesis; Embryo, Mammalian - cytology; Fibroblasts - cytology; Fibroblasts - metabolism; gene targeting; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; HEK293 Cells; HeLa Cells; histones; Histones - genetics; Histones - metabolism; Humans; Mice; Mice, Knockout; Microscopy, Fluorescence; Phosphorylation; Protein Binding; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; RNA Interference; stress response; Tetraploidy
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2012.04.029

Failure in cytokinesis, the final step in cell division, by generating tetra- and polyploidization promotes chromosomal instability, a hallmark of cancer. Here we show that HIPK2, a kinase involved in cell fate decisions in development and response to stress, controls cytokinesis and prevents tetraploidization through its effects on histone H2B. HIPK2 binds and phosphorylates histone H2B at S14 (H2B-S14P), and the two proteins colocalize at the midbody. HIPK2 depletion by targeted gene disruption or RNA interference results in loss of H2B-S14P at the midbody, prevention of cell cleavage, and tetra- and polyploidization. In HIPK2 null cells, restoration of wild-type HIPK2 activity or expression of a phosphomimetic H2B-S14D derivative abolishes cytokinesis defects and rescues cell proliferation, showing that H2B-S14P is required for a faithful cytokinesis. Overall, our data uncover mechanisms of a critical HIPK2 function in cytokinesis and in the prevention of tetraploidization. [Display omitted] ► HIPK2 deficiency promotes tetra- and polyploidization ► HIPK2 localizes at the midbody independently of the presence of chromosome bridges ► HIPK2 phosphorylates extrachromosomal histone H2B at the midbody ► HIPK2-mediated H2B-S14 phosphorylation is required for abscission