SET8 plays a role in controlling G₁/S transition by blocking lysine acetylation in histone through binding to H4 N-terminal tail

Abstract

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.

Memory CD4+T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors

“…This cohort of genes includes many that are involved in regulating apoptosis, signaling pathways, translation, cell migration, chemokine signaling, and metabolism. For example, 2°effectors expressed lower levels of genes associated with the suppression of DNA replication (setd8) (32) and dampening of cellular proliferation (lrig3) (33), as is consistent with the increased magnitude of 2°effector responses. Similarly, the higher expression in 1°effectors of genes such as satb2, a negative regulator of CD127 expression (34), and pcdh10, which can potentiate apoptosis (35), also is consistent with increased numbers of 2°effectors at the site of infection.…”

Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression

“…Consistent with this, we found that PR-Set7 is ubiquitinated by APC cdh1 during mitosis, resulting in proteolysis of PR-Set7. Interestingly, a recent study also determined that PR-Set7 ubiquitination by SCF Skp2 and subsequent degradation of PR-Set7 at G1 were associated with S-phase entry (Yin et al 2008). While the sustained decreased levels of PR-Set7 through S phase could be due to SCF Skp2 , it remains a formal possibility that other E3 ubiquitin ligases may also participate in the degradation of PR-Set7 during S-phase progression.…”

“…Subsequent studies demonstrated that PR-Set7-mediated H4K20me1 is required for chromatin compaction and transcriptional repression of specific genes, including some involved in mammalian differentiation (Biron et al 2004;Trojer et al 2007; Kalakonda et al 2008;Sims and Rice 2008). Recent studies indicate that PR-Set7 also plays an essential role in mammalian cell cycle progression (Karachentsev et al 2005;Jorgensen et al 2007;Tardat et al 2007;Houston et al 2008;Huen et al 2008;Yin et al 2008). The loss of PR-Set7 results in a G2 arrest in human cells, and PRSet7 À/À mice are embryonic-lethal, arresting at the eightcell stage (Houston et al 2008;Oda et al 2009).…”

A new layer of degradation mechanism for PR-Set7/Set8 during cell cycle

“…1,2 Set8 is critically involved in multiple cellular processes including transcription regulation, cell cycle, DNA repair, genome integrity and tumor metastasis. 3 The biological function of Set8 in cell cycle is largely exerted through suppressing DNA replication. 3,4 Further studies identified that Set8 could methylate non-histone proteins such as p53, Twist, Wnt-activated genes, PCNA (proliferating cell nuclear antigen), ERa (estrogen receptor) and AR (androgen receptor).…”

“…3 The biological function of Set8 in cell cycle is largely exerted through suppressing DNA replication. 3,4 Further studies identified that Set8 could methylate non-histone proteins such as p53, Twist, Wnt-activated genes, PCNA (proliferating cell nuclear antigen), ERa (estrogen receptor) and AR (androgen receptor). 5 These results indicate that Set8 may play a key role in the development and progression of cancers.…”