A new regulator of the cell cycle: the PR-Set7 histone methyltransferase

Abstract

The ability of eukaryotes to alter chromatin structure and function is modulated, in part, by histone-modifying enzymes and the post-translational modifications they create. One of these enzymes, PR-Set7/Set8/KMT5a, is the sole histone methyltransferase responsible for the monomethylation of histone H4 lysine 20 (H4K20me1) in higher eukaryotes. Both PR-Set7 and H4K20me1 were previously found to be tightly cell cycle regulated suggesting that they play an important, although unknown, role in cell cycle progression. Several recent reports reveal that PR-Set7 abundance is dynamically regulated during different cell cycle phases by distinct enzymes including cdk1/cyclinB, Cdc14, SCF(Skp2), CRL4(cdt2) and APC(cdh1). Importantly, these reports demonstrate that inappropriate levels of PR-Set7 result in profound cell cycle defects including the inability to initiate S phase, the re-replication of DNA and the improper timing of mitotic progression. Here, we summarize the significance of these new findings, raise some important questions that require further investigation and explore several possibilities of how PR-Set7 and methylated H4K20 may likely function as novel regulators of the cell cycle.

Figure 1

(A) Relative abundance of PR-Set7 and activity of the various enzymes that regulate PR-Set7 abundance (y-axis) during different cell cycle phases (x-axis). (B) Model of PR-Set7 regulation through the cell cycle. During G₁, PR-Set7 is targeted to specific loci resulting in H4K20me1 (closed red circles). Prior to S phase, PR-Set7 is ubiquitinated by SCF^Skp2 and degraded coincident with S phase entry. PR-Set7 is nearly undetectable during DNA replication as (1) PR-Set7 binds chromatin-bound PCNA via the PIP box resulting in ubiquitination by CRL4^cdt2 and subsequent degradation and (2) chromatin-free PR-Set7 is ubiquitinated by SCF^Skp2 and degraded. During G₂, PR-Set7 levels dramatically rise coincident with decreased SCF^Skp2 and CRL4^cdt2 activity resulting in H4K20me1 of unmodified nucleosomes (open red circles) on the newly replicated daughter strand (gray line). Following H4K20me1-associated chromatin condensation, chromosome-bound PR-Set7 is phosphorylated on serine 29 (S29) by cdk1/cyclinB during prophase to anaphase resulting in removal of PR-Set7 from mitotic chromosomes. This degradation-resistant form of PR-Set7 is dephosphorylated in anaphase by the Cdc14 phosphatases resulting in APC^cdh1-mediated ubiquitination and degradation of PR-Set7 as cell progress to G₁.