Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression.
Although the PR-Set7/Set8/KMT5a histone H4 Lys 20 monomethyltransferase (H4K20me1) plays an essential role in mammalian cell cycle progression, especially during G2/M, it remained unknown how PR-Set7 itself was regulated. In this study, we discovered the mechanisms that govern the dynamic regulation of PR-Set7 during mitosis, and that perturbation of these pathways results in defective mitotic progression. First, we found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase. The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis. This event is important for proper mitotic progression, as constitutive phosphorylation of PR-Set7 resulted in a substantial delay between metaphase and anaphase. Collectively, we elucidated the molecular mechanisms that control PR-Set7 protein levels during mitosis, and demonstrated that its orchestrated regulation is important for normal mitotic progression.
Wu
Shumin
S
Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
Wang
Weiping
W
Kong
Xiangduo
X
Congdon
Lauren M
LM
Yokomori
Kyoko
K
Kirschner
Marc W
MW
Rice
Judd C
JC
D000595:Amino Acid Sequence; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002477:Cells / Q000166:cytology* / Q000201:enzymology*; D002875:Chromosomes / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D008969:Molecular Sequence Data; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases; D016415:Sequence Alignment; D054875:Ubiquitination
D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; D016203:CDC2 Protein Kinase; D010744:Phosphoric Monoester Hydrolases; C120902:CDC14A protein, human; D017027:Protein Tyrosine Phosphatases