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TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts

Author

Listed:
  • John Fielden

    (University of Oxford)

  • Katherine Wiseman

    (University of Oxford)

  • Ignacio Torrecilla

    (University of Oxford)

  • Shudong Li

    (University of Oxford)

  • Samuel Hume

    (University of Oxford)

  • Shih-Chieh Chiang

    (University of Sheffield)

  • Annamaria Ruggiano

    (University of Oxford)

  • Abhay Narayan Singh

    (University of Oxford)

  • Raimundo Freire

    (Hospital Universitario de Canarias, Ofra s/n, La Cuesta
    Universidad de La Laguna
    Universidad Fernando Pessoa Canarias)

  • Sylvana Hassanieh

    (University of Oxford)

  • Enric Domingo

    (University of Oxford)

  • Iolanda Vendrell

    (University of Oxford
    University of Oxford)

  • Roman Fischer

    (University of Oxford)

  • Benedikt M. Kessler

    (University of Oxford)

  • Timothy S. Maughan

    (University of Oxford)

  • Sherif F. El-Khamisy

    (University of Sheffield)

  • Kristijan Ramadan

    (University of Oxford)

Abstract

Eukaryotic topoisomerase 1 (TOP1) regulates DNA topology to ensure efficient DNA replication and transcription. TOP1 is also a major driver of endogenous genome instability, particularly when its catalytic intermediate—a covalent TOP1-DNA adduct known as a TOP1 cleavage complex (TOP1cc)—is stabilised. TOP1ccs are highly cytotoxic and a failure to resolve them underlies the pathology of neurological disorders but is also exploited in cancer therapy where TOP1ccs are the target of widely used frontline anti-cancer drugs. A critical enzyme for TOP1cc resolution is the tyrosyl-DNA phosphodiesterase (TDP1), which hydrolyses the bond that links a tyrosine in the active site of TOP1 to a 3’ phosphate group on a single-stranded (ss)DNA break. However, TDP1 can only process small peptide fragments from ssDNA ends, raising the question of how the ~90 kDa TOP1 protein is processed upstream of TDP1. Here we find that TEX264 fulfils this role by forming a complex with the p97 ATPase and the SPRTN metalloprotease. We show that TEX264 recognises both unmodified and SUMO1-modifed TOP1 and initiates TOP1cc repair by recruiting p97 and SPRTN. TEX264 localises to the nuclear periphery, associates with DNA replication forks, and counteracts TOP1ccs during DNA replication. Altogether, our study elucidates the existence of a specialised repair complex required for upstream proteolysis of TOP1ccs and their subsequent resolution.

Suggested Citation

  • John Fielden & Katherine Wiseman & Ignacio Torrecilla & Shudong Li & Samuel Hume & Shih-Chieh Chiang & Annamaria Ruggiano & Abhay Narayan Singh & Raimundo Freire & Sylvana Hassanieh & Enric Domingo & , 2020. "TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15000-w
    DOI: 10.1038/s41467-020-15000-w
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    Cited by:

    1. Marika K. Kucińska & Juliette Fedry & Carmela Galli & Diego Morone & Andrea Raimondi & Tatiana Soldà & Friedrich Förster & Maurizio Molinari, 2023. "TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Zita Fábián & Ellen S. Kakulidis & Ivo A. Hendriks & Ulrike Kühbacher & Nicolai B. Larsen & Marta Oliva-Santiago & Junhui Wang & Xueyuan Leng & A. Barbara Dirac-Svejstrup & Jesper Q. Svejstrup & Micha, 2024. "PARP1-dependent DNA-protein crosslink repair," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Pedro Weickert & Hao-Yi Li & Maximilian J. Götz & Sophie Dürauer & Denitsa Yaneva & Shubo Zhao & Jacqueline Cordes & Aleida C. Acampora & Ignasi Forne & Axel Imhof & Julian Stingele, 2023. "SPRTN patient variants cause global-genome DNA-protein crosslink repair defects," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Yilun Sun & Simone A. Baechler & Xiaohu Zhang & Suresh Kumar & Valentina M. Factor & Yasuhiro Arakawa & Cindy H. Chau & Kanako Okamoto & Anup Parikh & Bob Walker & Yijun P. Su & Jiji Chen & Tabitha Ti, 2023. "Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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