SET8 plays a role in controlling G1/S transition by blocking lysine acetylation in histone through binding to H4 N-terminal tail.
We report evidence suggesting that methyltransferase SET8 plays a novel role in regulating cell cycle by suppressing DNA replication through histone binding. First, the distribution of SET8 is strongly cell cycle-dependent. SET8 was concentrated in the nucleus during G(1) and G(2) phases, and was excluded from the nucleus during S phase. Second, at G(1)/S transition, SET8 was degraded through ubiquitination via SCF/Skp2. Third, it was evident that the SET8 binds to the H4 N-terminal tail (H4NT) and blocks the acetylation of lysine residues K5, K8 and K12 of histone H4 during G(1). Such a blockage can hinder DNA replication. Fourth, SET8 binds to hypoacetylated but not hyperacetylated H4NT. Finally, overexpressing the histone-binding domain of SET8 appeared to suppress DNA replication and arrest the cell cycle before the G(1)/S transition. Taken together, these findings suggest that SET8 can be a negative regulator of DNA replication and the destruction of SET8 is required for the onset of S phase.
Yin
Yinliang
Y
Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Yu
Vivian C
VC
Zhu
Guang
G
Chang
Donald C
DC
D000107:Acetylation; D000595:Amino Acid Sequence; D015153:Blotting, Western; D005434:Flow Cytometry; D016193:G1 Phase / Q000502:physiology*; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008239:Lysine / Q000378:metabolism*; D008969:Molecular Sequence Data; D034741:RNA, Small Interfering / Q000235:genetics
D006657:Histones; D034741:RNA, Small Interfering; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; D008239:Lysine