HIPK2 controls cytokinesis and prevents tetraploidization by phosphorylating histone H2B at the midbody.
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-S14(P)), and the two proteins colocalize at the midbody. HIPK2 depletion by targeted gene disruption or RNA interference results in loss of H2B-S14(P) 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-S14(P) is required for a faithful cytokinesis. Overall, our data uncover mechanisms of a critical HIPK2 function in cytokinesis and in the prevention of tetraploidization.
Laboratorio di Oncogenesi Molecolare, Dipartimento di Oncologia Sperimentale, Istituto Nazionale dei Tumori Regina Elena, 00158 Rome, Italy. rinaldo@ifo.it
Cinzia
C
Rinaldo
Alice
A
Moncada
Alessandra
A
Gradi
Laura
L
Ciuffini
Donatella
D
D'Eliseo
Francesca
F
Siepi
Andrea
A
Prodosmo
Alessandra
A
Giorgi
Giovanna M
GM
Pierantoni
Francesco
F
Trapasso
Giulia
G
Guarguaglini
Armando
A
Bartolazzi
Enrico
E
Cundari
M Eugenia
ME
Schininà
Alfredo
A
Fusco
Silvia
S
Soddu
D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D048749:Cytokinesis; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D057891:Tetraploidy
D002352:Carrier Proteins; D006657:Histones; D049452:Green Fluorescent Proteins; C115114:HIPK2 protein, human; C492003:Hipk2 protein, mouse; D017346:Protein Serine-Threonine Kinases