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Mol Cell
2011 Oct 07;441:72-84. doi: 10.1016/j.molcel.2011.06.036.
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A genome-wide screen identifies p97 as an essential regulator of DNA damage-dependent CDT1 destruction.
Raman M
,
Havens CG
,
Walter JC
,
Harper JW
.
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Several proteins, including the replication licensing factor CDT1 and the histone methyltransferase SET8, are targeted for proteolysis during DNA replication and repair by the E3 ubiquitin ligase CRL4(CDT2). CRL4(CDT2) function is coupled to replication and repair because it only ubiquitinates substrates that associate with chromatin-bound PCNA. Here, we report a genome-wide siRNA screen that identifies multiple factors necessary for CDT1 destruction after UV irradiation. Among these, nucleotide excision repair factors promote CDT1 destruction due to a role in recruiting PCNA to damaged DNA. The COP9/Signalosome regulates CDT2 stability through CUL4 deneddylation. Finally, the p97 AAA(+)-ATPase and its cofactor UFD1 are required for proteasome-dependent removal of ubiquitinated CDT1 and SET8 from chromatin and their subsequent degradation both in vivo and in a Xenopus egg extract system in vitro. This study provides insight into and a resource for the further exploration of pathways that promote timely degradation of chromatin-associated CRL4(CDT2) substrates.
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
Abbas,
CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation.
2010,
Pubmed
Alexandru,
UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover.
2008,
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
Arias,
Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells.
2007,
Pubmed
Bai,
SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box.
1996,
Pubmed
Beskow,
A conserved unfoldase activity for the p97 AAA-ATPase in proteasomal degradation.
2009,
Pubmed
Centore,
CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase.
2010,
Pubmed
,
Xenbase
Cope,
COP9 signalosome: a multifunctional regulator of SCF and other cullin-based ubiquitin ligases.
2003,
Pubmed
Cope,
Targeted silencing of Jab1/Csn5 in human cells downregulates SCF activity through reduction of F-box protein levels.
2006,
Pubmed
DeLaBarre,
Central pore residues mediate the p97/VCP activity required for ERAD.
2006,
Pubmed
Finley,
Recognition and processing of ubiquitin-protein conjugates by the proteasome.
2009,
Pubmed
Fousteri,
Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects.
2008,
Pubmed
Ghislain,
Cdc48p interacts with Ufd3p, a WD repeat protein required for ubiquitin-mediated proteolysis in Saccharomyces cerevisiae.
1996,
Pubmed
Havens,
Docking of a specialized PIP Box onto chromatin-bound PCNA creates a degron for the ubiquitin ligase CRL4Cdt2.
2009,
Pubmed
,
Xenbase
Heo,
A stress-responsive system for mitochondrial protein degradation.
2010,
Pubmed
Heubes,
The AAA-ATPase p97-Ufd1-Npl4 is required for ERAD but not for spindle disassembly in Xenopus egg extracts.
2007,
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
Hu,
Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage.
2004,
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,
SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation.
2011,
Pubmed
Kim,
The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing.
2008,
Pubmed
Kim,
The CRL4Cdt2 ubiquitin ligase mediates the proteolysis of cyclin-dependent kinase inhibitor Xic1 through a direct association with PCNA.
2010,
Pubmed
,
Xenbase
Koegl,
A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly.
1999,
Pubmed
Lee,
ATP-dependent proteases degrade their substrates by processively unraveling them from the degradation signal.
2001,
Pubmed
Lovejoy,
DDB1 maintains genome integrity through regulation of Cdt1.
2006,
Pubmed
Matsuoka,
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.
2007,
Pubmed
Melixetian,
Loss of Geminin induces rereplication in the presence of functional p53.
2004,
Pubmed
Meyer,
Direct binding of ubiquitin conjugates by the mammalian p97 adaptor complexes, p47 and Ufd1-Npl4.
2002,
Pubmed
Miura,
Effect of XPA gene mutations on UV-induced immunostaining of PCNA in fibroblasts from xeroderma pigmentosum group A patients.
1996,
Pubmed
Moné,
Local UV-induced DNA damage in cell nuclei results in local transcription inhibition.
2001,
Pubmed
Muratani,
How the ubiquitin-proteasome system controls transcription.
2003,
Pubmed
Nishitani,
Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis.
2006,
Pubmed
Oda,
Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)-mediated PCNA-dependent degradation during DNA damage.
2010,
Pubmed
Prakash,
Substrate selection by the proteasome during degradation of protein complexes.
2009,
Pubmed
Ramadan,
Cdc48/p97 promotes reformation of the nucleus by extracting the kinase Aurora B from chromatin.
2007,
Pubmed
,
Xenbase
Ramanathan,
Revoking the cellular license to replicate: yet another AAA assignment.
2011,
Pubmed
Richly,
A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting.
2005,
Pubmed
Shibutani,
Intrinsic negative cell cycle regulation provided by PIP box- and Cul4Cdt2-mediated destruction of E2f1 during S phase.
2008,
Pubmed
Vembar,
One step at a time: endoplasmic reticulum-associated degradation.
2008,
Pubmed
Verma,
Cdc48/p97 mediates UV-dependent turnover of RNA Pol II.
2011,
Pubmed
Wee,
CSN facilitates Cullin-RING ubiquitin ligase function by counteracting autocatalytic adapter instability.
2005,
Pubmed
Wohlschlegel,
Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.
2000,
Pubmed
,
Xenbase
Zhong,
CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing.
2003,
Pubmed
