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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,
C. elegans CUL-4 prevents rereplication by promoting the nuclear export of CDC-6 via a CKI-1-dependent pathway.
2007,
Pubmed
Kim,
The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing.
2008,
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
O'Farrell,
Triggering the all-or-nothing switch into mitosis.
2001,
Pubmed
Oda,
Monomethylation of histone H4-lysine 20 is involved in chromosome structure and stability and is essential for mouse development.
2009,
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
