DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks
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DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks. / Mosbech, Anna; Gibbs-Seymour, Ian; Kagias, Konstantinos; Thorslund, Tina; Beli, Petra; Povlsen, Lou; Nielsen, Sofie Vincents; Smedegaard, Stine; Sedgwick, Garry; Lukas, Claudia; Hartmann-Petersen, Rasmus; Lukas, Jiri; Choudhary, Chuna Ram; Pocock, Roger David John; Bekker-Jensen, Simon; Mailand, Niels.
In: Nature Structural and Molecular Biology, Vol. 19, No. 11, 2012, p. 1084-92.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks
AU - Mosbech, Anna
AU - Gibbs-Seymour, Ian
AU - Kagias, Konstantinos
AU - Thorslund, Tina
AU - Beli, Petra
AU - Povlsen, Lou
AU - Nielsen, Sofie Vincents
AU - Smedegaard, Stine
AU - Sedgwick, Garry
AU - Lukas, Claudia
AU - Hartmann-Petersen, Rasmus
AU - Lukas, Jiri
AU - Choudhary, Chuna Ram
AU - Pocock, Roger David John
AU - Bekker-Jensen, Simon
AU - Mailand, Niels
N1 - 10.1038/nsmb.2395
PY - 2012
Y1 - 2012
N2 - Ubiquitin-mediated processes orchestrate critical DNA-damage signaling and repair pathways. We identify human DVC1 (C1orf124; Spartan) as a cell cycle-regulated anaphase-promoting complex (APC) substrate that accumulates at stalled replication forks. DVC1 recruitment to sites of replication stress requires its ubiquitin-binding UBZ domain and PCNA-binding PIP box motif but is independent of RAD18-mediated PCNA monoubiquitylation. Via a conserved SHP box, DVC1 recruits the ubiquitin-selective chaperone p97 to blocked replication forks, which may facilitate p97-dependent removal of translesion synthesis (TLS) DNA polymerase η (Pol η) from monoubiquitylated PCNA. DVC1 knockdown enhances UV light-induced mutagenesis, and depletion of human DVC1 or the Caenorhabditis elegans ortholog DVC-1 causes hypersensitivity to replication stress-inducing agents. Our findings establish DVC1 as a DNA damage-targeting p97 adaptor that protects cells from deleterious consequences of replication blocks and suggest an important role of p97 in ubiquitin-dependent regulation of TLS.
AB - Ubiquitin-mediated processes orchestrate critical DNA-damage signaling and repair pathways. We identify human DVC1 (C1orf124; Spartan) as a cell cycle-regulated anaphase-promoting complex (APC) substrate that accumulates at stalled replication forks. DVC1 recruitment to sites of replication stress requires its ubiquitin-binding UBZ domain and PCNA-binding PIP box motif but is independent of RAD18-mediated PCNA monoubiquitylation. Via a conserved SHP box, DVC1 recruits the ubiquitin-selective chaperone p97 to blocked replication forks, which may facilitate p97-dependent removal of translesion synthesis (TLS) DNA polymerase η (Pol η) from monoubiquitylated PCNA. DVC1 knockdown enhances UV light-induced mutagenesis, and depletion of human DVC1 or the Caenorhabditis elegans ortholog DVC-1 causes hypersensitivity to replication stress-inducing agents. Our findings establish DVC1 as a DNA damage-targeting p97 adaptor that protects cells from deleterious consequences of replication blocks and suggest an important role of p97 in ubiquitin-dependent regulation of TLS.
KW - Adenosine Triphosphatases
KW - Anaphase-Promoting Complex-Cyclosome
KW - Animals
KW - Caenorhabditis elegans
KW - Cell Cycle Proteins
KW - DNA Damage
KW - DNA Replication
KW - DNA-Binding Proteins
KW - DNA-Directed DNA Polymerase
KW - Flow Cytometry
KW - Gene Knockdown Techniques
KW - Green Fluorescent Proteins
KW - Humans
KW - Immunoblotting
KW - Immunoprecipitation
KW - Mass Spectrometry
KW - Mutagenesis
KW - Plasmids
KW - Proliferating Cell Nuclear Antigen
KW - RNA Interference
KW - RNA, Small Interfering
KW - Signal Transduction
KW - Ubiquitin
KW - Ubiquitin-Protein Ligase Complexes
U2 - 10.1038/nsmb.2395
DO - 10.1038/nsmb.2395
M3 - Journal article
C2 - 23042605
VL - 19
SP - 1084
EP - 1092
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
IS - 11
ER -
ID: 42018480