CRL4Cdt2 Regulates Cell Proliferation and Histone Gene Expression by Targeting PR-Set7/Set8 for Degradation

Abstract

SUMMARY PR-Set7/Set8 is a cell cycle-regulated enzyme that monomethylates lysine 20 of histone H4 (H4K20). Set8 and monomethylated H4K20 are virtually undetectable during G1 and S phases of the cell cycle but increase in late S and in G2. We identify CRL4Cdt2 as the principal E3 ubiquitin ligase responsible for Set8 proteolytic degradation in the S-phase of the cell cycle, which requires Set8-PCNA interaction. Inactivation of the CRL4-Cdt2-PCNA-Set8 degradation axis results in (a) DNA damage and the induction of tumor suppressor p53 and p53-transactivated pro-apoptotic genes, (b) delayed progression through G2 phase of the cell cycle due to activation of the G2/M check-point, (c) specific repression of histone gene transcription and depletion of the histone proteins, and (d) repression of E2F1-dependent gene transcription. These results demonstrate a central role of CRL4Cdt2-dependent cell cycle regulation of Set8 for the maintenance of a stable epigenetic state essential for cell viability.

Epigenetic inheritance: Uncontested?

“…This was confirmed by an independent study [52]. These results are consistent with the findings that H4K20me2-3, established by the Suv4-20 enzymes, requires H4K20me1 [53], which is catalyzed by PR-Set7, whose expression is cell cycle-regulated and present from G2 to early G1 [54][55][56][57][58].…”

CDK1-dependent Inhibition of the E3 Ubiquitin Ligase CRL4CDT2 Ensures Robust Transition from S Phase to Mitosis

“…CDT2 Substrate Accumulation Occurs in Late S Phase Prior to PCNA Unloading-Previous work described replication-coupled destruction of CRL4 CDT2 substrates and further documented their robust accumulation at later cell cycle stages (5,11,19,37) illustrated in Fig. 1A.…”

Thymine DNA Glycosylase Is a CRL4Cdt2 Substrate

“…Cdt2 also targets the histone methyltransferase Set8 (7,8) and the cyclin-dependent kinase inhibitor p21 (9,10). In both cases, destruction is thought to inhibit licensing in S phase.…”