Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway

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

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Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway. / Liu, Julio C Y; Kühbacher, Ulrike; Larsen, Nicolai B; Borgermann, Nikoline; Garvanska, Dimitriya H; Hendriks, Ivo A; Ackermann, Leena; Haahr, Peter; Gallina, Irene; Guérillon, Claire; Branigan, Emma; Hay, Ronald T.; Azuma, Yoshiaki; Nielsen, Michael Lund; Duxin, Julien P; Mailand, Niels.

In: E M B O Journal, Vol. 40, e107413, 2021.

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

Harvard

Liu, JCY, Kühbacher, U, Larsen, NB, Borgermann, N, Garvanska, DH, Hendriks, IA, Ackermann, L, Haahr, P, Gallina, I, Guérillon, C, Branigan, E, Hay, RT, Azuma, Y, Nielsen, ML, Duxin, JP & Mailand, N 2021, 'Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway', E M B O Journal, vol. 40, e107413. https://doi.org/10.15252/embj.2020107413

APA

Liu, J. C. Y., Kühbacher, U., Larsen, N. B., Borgermann, N., Garvanska, D. H., Hendriks, I. A., Ackermann, L., Haahr, P., Gallina, I., Guérillon, C., Branigan, E., Hay, R. T., Azuma, Y., Nielsen, M. L., Duxin, J. P., & Mailand, N. (2021). Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway. E M B O Journal, 40, [e107413]. https://doi.org/10.15252/embj.2020107413

Vancouver

Liu JCY, Kühbacher U, Larsen NB, Borgermann N, Garvanska DH, Hendriks IA et al. Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway. E M B O Journal. 2021;40. e107413. https://doi.org/10.15252/embj.2020107413

Author

Liu, Julio C Y ; Kühbacher, Ulrike ; Larsen, Nicolai B ; Borgermann, Nikoline ; Garvanska, Dimitriya H ; Hendriks, Ivo A ; Ackermann, Leena ; Haahr, Peter ; Gallina, Irene ; Guérillon, Claire ; Branigan, Emma ; Hay, Ronald T. ; Azuma, Yoshiaki ; Nielsen, Michael Lund ; Duxin, Julien P ; Mailand, Niels. / Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway. In: E M B O Journal. 2021 ; Vol. 40.

Bibtex

@article{0de1d5cadaae4076bf05071bba3f549d,
title = "Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway",
abstract = "DNA-protein crosslinks (DPCs) obstruct essential DNA transactions, posing a serious threat to genome stability and functionality. DPCs are proteolytically processed in a ubiquitin- and DNA replication-dependent manner by SPRTN and the proteasome but can also be resolved via targeted SUMOylation. However, the mechanistic basis of SUMO-mediated DPC resolution and its interplay with replication-coupled DPC repair remain unclear. Here, we show that the SUMO-targeted ubiquitin ligase RNF4 defines a major pathway for ubiquitylation and proteasomal clearance of SUMOylated DPCs in the absence of DNA replication. Importantly, SUMO modifications of DPCs neither stimulate nor inhibit their rapid DNA replication-coupled proteolysis. Instead, DPC SUMOylation provides a critical salvage mechanism to remove DPCs formed after DNA replication, as DPCs on duplex DNA do not activate interphase DNA damage checkpoints. Consequently, in the absence of the SUMO-RNF4 pathway cells are able to enter mitosis with a high load of unresolved DPCs, leading to defective chromosome segregation and cell death. Collectively, these findings provide mechanistic insights into SUMO-driven pathways underlying replication-independent DPC resolution and highlight their critical importance in maintaining chromosome stability and cellular fitness.",
author = "Liu, {Julio C Y} and Ulrike K{\"u}hbacher and Larsen, {Nicolai B} and Nikoline Borgermann and Garvanska, {Dimitriya H} and Hendriks, {Ivo A} and Leena Ackermann and Peter Haahr and Irene Gallina and Claire Gu{\'e}rillon and Emma Branigan and Hay, {Ronald T.} and Yoshiaki Azuma and Nielsen, {Michael Lund} and Duxin, {Julien P} and Niels Mailand",
note = "{\textcopyright} 2021 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2021",
doi = "10.15252/embj.2020107413",
language = "English",
volume = "40",
journal = "E M B O Journal",
issn = "0261-4189",
publisher = "Wiley-Blackwell",

}

RIS

TY - JOUR

T1 - Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway

AU - Liu, Julio C Y

AU - Kühbacher, Ulrike

AU - Larsen, Nicolai B

AU - Borgermann, Nikoline

AU - Garvanska, Dimitriya H

AU - Hendriks, Ivo A

AU - Ackermann, Leena

AU - Haahr, Peter

AU - Gallina, Irene

AU - Guérillon, Claire

AU - Branigan, Emma

AU - Hay, Ronald T.

AU - Azuma, Yoshiaki

AU - Nielsen, Michael Lund

AU - Duxin, Julien P

AU - Mailand, Niels

N1 - © 2021 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2021

Y1 - 2021

N2 - DNA-protein crosslinks (DPCs) obstruct essential DNA transactions, posing a serious threat to genome stability and functionality. DPCs are proteolytically processed in a ubiquitin- and DNA replication-dependent manner by SPRTN and the proteasome but can also be resolved via targeted SUMOylation. However, the mechanistic basis of SUMO-mediated DPC resolution and its interplay with replication-coupled DPC repair remain unclear. Here, we show that the SUMO-targeted ubiquitin ligase RNF4 defines a major pathway for ubiquitylation and proteasomal clearance of SUMOylated DPCs in the absence of DNA replication. Importantly, SUMO modifications of DPCs neither stimulate nor inhibit their rapid DNA replication-coupled proteolysis. Instead, DPC SUMOylation provides a critical salvage mechanism to remove DPCs formed after DNA replication, as DPCs on duplex DNA do not activate interphase DNA damage checkpoints. Consequently, in the absence of the SUMO-RNF4 pathway cells are able to enter mitosis with a high load of unresolved DPCs, leading to defective chromosome segregation and cell death. Collectively, these findings provide mechanistic insights into SUMO-driven pathways underlying replication-independent DPC resolution and highlight their critical importance in maintaining chromosome stability and cellular fitness.

AB - DNA-protein crosslinks (DPCs) obstruct essential DNA transactions, posing a serious threat to genome stability and functionality. DPCs are proteolytically processed in a ubiquitin- and DNA replication-dependent manner by SPRTN and the proteasome but can also be resolved via targeted SUMOylation. However, the mechanistic basis of SUMO-mediated DPC resolution and its interplay with replication-coupled DPC repair remain unclear. Here, we show that the SUMO-targeted ubiquitin ligase RNF4 defines a major pathway for ubiquitylation and proteasomal clearance of SUMOylated DPCs in the absence of DNA replication. Importantly, SUMO modifications of DPCs neither stimulate nor inhibit their rapid DNA replication-coupled proteolysis. Instead, DPC SUMOylation provides a critical salvage mechanism to remove DPCs formed after DNA replication, as DPCs on duplex DNA do not activate interphase DNA damage checkpoints. Consequently, in the absence of the SUMO-RNF4 pathway cells are able to enter mitosis with a high load of unresolved DPCs, leading to defective chromosome segregation and cell death. Collectively, these findings provide mechanistic insights into SUMO-driven pathways underlying replication-independent DPC resolution and highlight their critical importance in maintaining chromosome stability and cellular fitness.

U2 - 10.15252/embj.2020107413

DO - 10.15252/embj.2020107413

M3 - Journal article

C2 - 34346517

VL - 40

JO - E M B O Journal

JF - E M B O Journal

SN - 0261-4189

M1 - e107413

ER -

ID: 275948647