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

Research output: Contribution to journal › Journal article › Research › peer-review

148 Citations (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.

Original language	English
Journal	Nature Structural and Molecular Biology
Volume	19
Issue number	11
Pages (from-to)	1084-92
Number of pages	9
ISSN	1545-9993
DOIs	https://doi.org/10.1038/nsmb.2395
Publication status	Published - 2012

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

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10.1038/nsmb.2395

Cite this

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

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 › Research › peer-review

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, vol. 19, no. 11, pp. 1084-92. https://doi.org/10.1038/nsmb.2395

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. / DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks. In: Nature Structural and Molecular Biology. 2012 ; Vol. 19, No. 11. pp. 1084-92.

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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.",

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AU - Nielsen, Sofie Vincents

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AU - Lukas, Claudia

AU - Hartmann-Petersen, Rasmus

AU - Lukas, Jiri

AU - Choudhary, Chuna Ram

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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.

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JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

SN - 1545-9993

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