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CRL4Cdt2-Mediated Destruction of the Histone Methyltransferase Set8 Prevents Premature Chromatin Compaction in S Phase

2010; Elsevier BV; Volume: 40; Issue: 1 Linguagem: Inglês

10.1016/j.molcel.2010.09.015

1097-4164

Richard C. Centore, Courtney G. Havens, Amity L. Manning, Ju-Mei Li, Rachel Litman Flynn, Alice Tse, Jianping Jin, Nicholas J. Dyson, Johannes C. Walter, Lee Zou,

Genomics and Chromatin Dynamics

The proper coordination between DNA replication and mitosis during cell-cycle progression is crucial for genomic stability. During G2 and mitosis, Set8 catalyzes monomethylation of histone H4 on lysine 20 (H4K20me1), which promotes chromatin compaction. Set8 levels decline in S phase, but why and how this occurs is unclear. Here, we show that Set8 is targeted for proteolysis in S phase and in response to DNA damage by the E3 ubiquitin ligase, CRL4Cdt2. Set8 ubiquitylation occurs on chromatin and is coupled to DNA replication via a specific degron in Set8 that binds PCNA. Inactivation of CRL4Cdt2 leads to Set8 stabilization and aberrant H4K20me1 accumulation in replicating cells. Transient S phase expression of a Set8 mutant lacking the degron promotes premature H4K20me1 accumulation and chromatin compaction, and triggers a checkpoint-mediated G2 arrest. Thus, CRL4Cdt2-dependent destruction of Set8 in S phase preserves genome stability by preventing aberrant chromatin compaction during DNA synthesis.