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Mol Cell
2010 Oct 08;401:22-33. doi: 10.1016/j.molcel.2010.09.015.
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CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase.
Centore RC, Havens CG, Manning AL, Li JM, Flynn RL, Tse A, Jin J, Dyson NJ, Walter JC, Zou L.
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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, CRL4(Cdt2). Set8 ubiquitylation occurs on chromatin and is coupled to DNA replication via a specific degron in Set8 that binds PCNA. Inactivation of CRL4(Cdt2) 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, CRL4(Cdt2)-dependent destruction of Set8 in S phase preserves genome stability by preventing aberrant chromatin compaction during DNA synthesis.
Abbas,
PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex.
2008, Pubmed
Abbas,
PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex.
2008,
Pubmed Angers,
Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery.
2006,
Pubmed Arias,
Replication-dependent destruction of Cdt1 limits DNA replication to a single round per cell cycle in Xenopus egg extracts.
2005,
Pubmed
,
Xenbase Arias,
PCNA functions as a molecular platform to trigger Cdt1 destruction and prevent re-replication.
2006,
Pubmed
,
Xenbase Brown,
ATR disruption leads to chromosomal fragmentation and early embryonic lethality.
2000,
Pubmed Congdon,
PR-Set7-mediated monomethylation of histone H4 lysine 20 at specific genomic regions induces transcriptional repression.
2010,
Pubmed David,
Cell cycle: Disposing of SETD8.
2010,
Pubmed Fang,
Purification and functional characterization of SET8, a nucleosomal histone H4-lysine 20-specific methyltransferase.
2002,
Pubmed Havens,
Docking of a specialized PIP Box onto chromatin-bound PCNA creates a degron for the ubiquitin ligase CRL4Cdt2.
2009,
Pubmed
,
Xenbase Higa,
Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint.
2003,
Pubmed Higa,
L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1 proteolysis in response to DNA damage.
2006,
Pubmed Hirota,
Distinct functions of condensin I and II in mitotic chromosome assembly.
2004,
Pubmed Houston,
Catalytic function of the PR-Set7 histone H4 lysine 20 monomethyltransferase is essential for mitotic entry and genomic stability.
2008,
Pubmed Hu,
Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage.
2004,
Pubmed Hu,
An evolutionarily conserved function of proliferating cell nuclear antigen for Cdt1 degradation by the Cul4-Ddb1 ubiquitin ligase in response to DNA damage.
2006,
Pubmed Huen,
Direct interaction between SET8 and proliferating cell nuclear antigen couples H4-K20 methylation with DNA replication.
2008,
Pubmed Jin,
A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1.
2006,
Pubmed
,
Xenbase Jørgensen,
The histone methyltransferase SET8 is required for S-phase progression.
2007,
Pubmed Karachentsev,
PR-Set7-dependent methylation of histone H4 Lys 20 functions in repression of gene expression and is essential for mitosis.
2005,
Pubmed Kim,
The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing.
2008,
Pubmed Kim,
C. elegans CUL-4 prevents rereplication by promoting the nuclear export of CDC-6 via a CKI-1-dependent pathway.
2007,
Pubmed Kondo,
Rapid degradation of Cdt1 upon UV-induced DNA damage is mediated by SCFSkp2 complex.
2004,
Pubmed Lee,
SETting the clock for histone H4 monomethylation.
2010,
Pubmed Li,
The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation.
2003,
Pubmed Liu,
PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression.
2010,
Pubmed Lovejoy,
DDB1 maintains genome integrity through regulation of Cdt1.
2006,
Pubmed Nghiem,
ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation.
2001,
Pubmed Nishioka,
PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin.
2002,
Pubmed Nishitani,
Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis.
2006,
Pubmed Nishitani,
CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation.
2008,
Pubmed Oda,
Monomethylation of histone H4-lysine 20 is involved in chromosome structure and stability and is essential for mouse development.
2009,
Pubmed O'Farrell,
Triggering the all-or-nothing switch into mitosis.
2001,
Pubmed Paulsen,
A genome-wide siRNA screen reveals diverse cellular processes and pathways that mediate genome stability.
2009,
Pubmed Rice,
Mitotic-specific methylation of histone H4 Lys 20 follows increased PR-Set7 expression and its localization to mitotic chromosomes.
2002,
Pubmed Sakaguchi,
Aberrant monomethylation of histone H4 lysine 20 activates the DNA damage checkpoint in Drosophila melanogaster.
2007,
Pubmed Sansam,
DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint.
2006,
Pubmed Schotta,
A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse.
2008,
Pubmed Senga,
PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination.
2006,
Pubmed Shi,
Modulation of p53 function by SET8-mediated methylation at lysine 382.
2007,
Pubmed Takeda,
Degradation of Cdt1 during S phase is Skp2-independent and is required for efficient progression of mammalian cells through S phase.
2005,
Pubmed Tardat,
PR-Set7-dependent lysine methylation ensures genome replication and stability through S phase.
2007,
Pubmed Trojer,
L3MBTL1, a histone-methylation-dependent chromatin lock.
2007,
Pubmed Walter,
Regulated chromosomal DNA replication in the absence of a nucleus.
1998,
Pubmed
,
Xenbase Yin,
SET8 plays a role in controlling G1/S transition by blocking lysine acetylation in histone through binding to H4 N-terminal tail.
2008,
Pubmed Zhong,
CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing.
2003,
Pubmed Zou,
Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.
2003,
Pubmed
