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Mol Cell
2016 Oct 06;641:189-198. doi: 10.1016/j.molcel.2016.08.037.
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VCP/p97 Extracts Sterically Trapped Ku70/80 Rings from DNA in Double-Strand Break Repair.
van den Boom J
,
Wolf M
,
Weimann L
,
Schulze N
,
Li F
,
Kaschani F
,
Riemer A
,
Zierhut C
,
Kaiser M
,
Iliakis G
,
Funabiki H
,
Meyer H
.
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During DNA double-strand break (DSB) repair, the ring-shaped Ku70/80 complex becomes trapped on DNA and needs to be actively extracted, but it has remained unclear what provides the required energy. By means of reconstitution of DSB repair on beads, we demonstrate here that DNA-locked Ku rings are released by the AAA-ATPase p97. To achieve this, p97 requires ATP hydrolysis, cooperates with the Ufd1-Npl4 ubiquitin-adaptor complex, and specifically targets Ku80 that is modified by K48-linked ubiquitin chains. In U2OS cells, chemical inhibition of p97 or siRNA-mediated depletion of p97 or its adapters impairs Ku80 removal after non-homologous end joining of DSBs. Moreover, this inhibition attenuates early steps in homologous recombination, consistent with p97-driven Ku release also affecting repair pathway choice. Thus, our data answer a central question regarding regulation of Ku in DSB repair and illustrate the ability of p97 to segregate even tightly bound protein complexes for release from DNA.
Acs,
The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks.
2011, Pubmed
Acs,
The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks.
2011,
Pubmed
Alexandru,
UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover.
2008,
Pubmed
Bekker-Jensen,
The ubiquitin- and SUMO-dependent signaling response to DNA double-strand breaks.
2011,
Pubmed
Bergink,
Role of Cdc48/p97 as a SUMO-targeted segregase curbing Rad51-Rad52 interaction.
2013,
Pubmed
Blier,
Binding of Ku protein to DNA. Measurement of affinity for ends and demonstration of binding to nicks.
1993,
Pubmed
Britton,
A new method for high-resolution imaging of Ku foci to decipher mechanisms of DNA double-strand break repair.
2013,
Pubmed
Ciccia,
The DNA damage response: making it safe to play with knives.
2010,
Pubmed
Dantuma,
Should I stay or should I go: VCP/p97-mediated chromatin extraction in the DNA damage response.
2014,
Pubmed
Di Virgilio,
Repair of double-strand breaks by nonhomologous end joining in the absence of Mre11.
2005,
Pubmed
,
Xenbase
Feng,
The E3 ligase RNF8 regulates KU80 removal and NHEJ repair.
2012,
Pubmed
Franz,
Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression.
2016,
Pubmed
Ismail,
The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice.
2015,
Pubmed
Jackson,
The DNA-damage response in human biology and disease.
2009,
Pubmed
Jackson,
Regulation of DNA damage responses by ubiquitin and SUMO.
2013,
Pubmed
Jentsch,
Cdc48 (p97): a "molecular gearbox" in the ubiquitin pathway?
2007,
Pubmed
Krishna,
The bridge-region of the Ku superfamily is an atypical zinc ribbon domain.
2010,
Pubmed
Labhart,
Nonhomologous DNA end joining in cell-free systems.
1999,
Pubmed
,
Xenbase
Lieber,
Nonhomologous DNA end joining (NHEJ) and chromosomal translocations in humans.
2010,
Pubmed
Magnaghi,
Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death.
2013,
Pubmed
Meerang,
The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks.
2011,
Pubmed
Meyer,
Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system.
2012,
Pubmed
Paillard,
Analysis of the mechanism of interaction of simian Ku protein with DNA.
1991,
Pubmed
Postow,
Ku80 removal from DNA through double strand break-induced ubiquitylation.
2008,
Pubmed
,
Xenbase
Postow,
An SCF complex containing Fbxl12 mediates DNA damage-induced Ku80 ubiquitylation.
2013,
Pubmed
,
Xenbase
Raman,
A genome-wide screen identifies p97 as an essential regulator of DNA damage-dependent CDT1 destruction.
2011,
Pubmed
,
Xenbase
Riemer,
The p97-Ufd1-Npl4 ATPase complex ensures robustness of the G2/M checkpoint by facilitating CDC25A degradation.
2014,
Pubmed
Schmidt,
Systematic E2 screening reveals a UBE2D-RNF138-CtIP axis promoting DNA repair.
2015,
Pubmed
Stolz,
Cdc48: a power machine in protein degradation.
2011,
Pubmed
Sun,
Human Ku70/80 protein blocks exonuclease 1-mediated DNA resection in the presence of human Mre11 or Mre11/Rad50 protein complex.
2012,
Pubmed
Walker,
Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair.
2001,
Pubmed
Ye,
Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains.
2003,
Pubmed
