DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks

Anna Mosbech; Ian Gibbs-Seymour; Konstantinos Kagias; Tina Thorslund; Petra Beli; Lou Povlsen; Sofie Vincents Nielsen; Stine Smedegaard; Garry Sedgwick; Claudia Lukas; Rasmus Hartmann-Petersen; Jiri Lukas; Chuna Ram Choudhary; Roger David John Pocock; Simon Bekker-Jensen; Niels Mailand

doi:10.1038/nsmb.2395

DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks

Anna Mosbech, Ian Gibbs-Seymour, Konstantinos Kagias, Tina Thorslund, Petra Beli, Lou Povlsen, Sofie Vincents Nielsen, Stine Smedegaard, Garry Sedgwick, Claudia Lukas, Rasmus Hartmann-Petersen, Jiri Lukas, Chuna Ram Choudhary, Roger David John Pocock, Simon Bekker-Jensen, Niels Mailand

120 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Nature Structural and Molecular Biology
Vol/bind	19
Udgave nummer	11
Sider (fra-til)	1084-92
Antal sider	9
ISSN	1545-9993
DOI	https://doi.org/10.1038/nsmb.2395
Status	Udgivet - nov. 2012

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10.1038/nsmb.2395

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Mosbech, A., Gibbs-Seymour, I., Kagias, K., Thorslund, T., Beli, P., Povlsen, L., Nielsen, S. V., Smedegaard, S., Sedgwick, G., Lukas, C., Hartmann-Petersen, R., Lukas, J., Choudhary, C. R., Pocock, R. D. J., Bekker-Jensen, S., & Mailand, N. (2012). DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks. Nature Structural and Molecular Biology, 19(11), 1084-92. https://doi.org/10.1038/nsmb.2395

Mosbech, A, Gibbs-Seymour, I, Kagias, K, Thorslund, T, Beli, P, Povlsen, L, Nielsen, SV, Smedegaard, S, Sedgwick, G, Lukas, C , Hartmann-Petersen, R , Lukas, J , Choudhary, CR, Pocock, RDJ, Bekker-Jensen, S & Mailand, N 2012, 'DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks', Nature Structural and Molecular Biology, bind 19, nr. 11, s. 1084-92. https://doi.org/10.1038/nsmb.2395

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title = "DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks",

abstract = "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.",

keywords = "Adenosine Triphosphatases, Anaphase-Promoting Complex-Cyclosome, Animals, Caenorhabditis elegans, Cell Cycle Proteins, DNA Damage, DNA Replication, DNA-Binding Proteins, DNA-Directed DNA Polymerase, Flow Cytometry, Gene Knockdown Techniques, Green Fluorescent Proteins, Humans, Immunoblotting, Immunoprecipitation, Mass Spectrometry, Mutagenesis, Plasmids, Proliferating Cell Nuclear Antigen, RNA Interference, RNA, Small Interfering, Signal Transduction, Ubiquitin, Ubiquitin-Protein Ligase Complexes",

author = "Anna Mosbech and Ian Gibbs-Seymour and Konstantinos Kagias and Tina Thorslund and Petra Beli and Lou Povlsen and Nielsen, {Sofie Vincents} and Stine Smedegaard and Garry Sedgwick and Claudia Lukas and Rasmus Hartmann-Petersen and Jiri Lukas and Choudhary, {Chuna Ram} and Pocock, {Roger David John} and Simon Bekker-Jensen and Niels Mailand",

note = "10.1038/nsmb.2395",

year = "2012",

month = nov,

doi = "10.1038/nsmb.2395",

language = "English",

volume = "19",

pages = "1084--92",

journal = "Nature Structural and Molecular Biology",

issn = "1545-9993",

publisher = "nature publishing group",

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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 - 2012/11

Y1 - 2012/11

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

SN - 1545-9993

VL - 19

SP - 1084

EP - 1092

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 11

ER -

DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks

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