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TRAIP is a master regulator of DNA interstrand crosslink repair

Author

Listed:
  • R. Alex Wu

    (Harvard Medical School)

  • Daniel R. Semlow

    (Harvard Medical School)

  • Ashley N. Kamimae-Lanning

    (Cambridge Biomedical Campus)

  • Olga V. Kochenova

    (Harvard Medical School)

  • Gheorghe Chistol

    (Harvard Medical School)

  • Michael R. Hodskinson

    (Cambridge Biomedical Campus)

  • Ravindra Amunugama

    (Harvard Medical School)

  • Justin L. Sparks

    (Harvard Medical School)

  • Meng Wang

    (Cambridge Biomedical Campus
    University of Cambridge)

  • Lin Deng

    (Harvard Medical School
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Claudia A. Mimoso

    (Harvard Medical School)

  • Emily Low

    (Harvard Medical School)

  • Ketan J. Patel

    (Cambridge Biomedical Campus
    University of Cambridge, Addenbrooke’s Hospital)

  • Johannes C. Walter

    (Harvard Medical School
    Howard Hughes Medical Institute)

Abstract

Cells often use multiple pathways to repair the same DNA lesion, and the choice of pathway has substantial implications for the fidelity of genome maintenance. DNA interstrand crosslinks covalently link the two strands of DNA, and thereby block replication and transcription; the cytotoxicity of these crosslinks is exploited for chemotherapy. In Xenopus egg extracts, the collision of replication forks with interstrand crosslinks initiates two distinct repair pathways. NEIL3 glycosylase can cleave the crosslink1; however, if this fails, Fanconi anaemia proteins incise the phosphodiester backbone that surrounds the interstrand crosslink, generating a double-strand-break intermediate that is repaired by homologous recombination2. It is not known how the simpler NEIL3 pathway is prioritized over the Fanconi anaemia pathway, which can cause genomic rearrangements. Here we show that the E3 ubiquitin ligase TRAIP is required for both pathways. When two replisomes converge at an interstrand crosslink, TRAIP ubiquitylates the replicative DNA helicase CMG (the complex of CDC45, MCM2–7 and GINS). Short ubiquitin chains recruit NEIL3 through direct binding, whereas longer chains are required for the unloading of CMG by the p97 ATPase, which enables the Fanconi anaemia pathway. Thus, TRAIP controls the choice between the two known pathways of replication-coupled interstrand-crosslink repair. These results, together with our other recent findings3,4 establish TRAIP as a master regulator of CMG unloading and the response of the replisome to obstacles.

Suggested Citation

  • R. Alex Wu & Daniel R. Semlow & Ashley N. Kamimae-Lanning & Olga V. Kochenova & Gheorghe Chistol & Michael R. Hodskinson & Ravindra Amunugama & Justin L. Sparks & Meng Wang & Lin Deng & Claudia A. Mim, 2019. "TRAIP is a master regulator of DNA interstrand crosslink repair," Nature, Nature, vol. 567(7747), pages 267-272, March.
  • Handle: RePEc:nat:nature:v:567:y:2019:i:7747:d:10.1038_s41586-019-1002-0
    DOI: 10.1038/s41586-019-1002-0
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    Cited by:

    1. Olga V. Kochenova & Sirisha Mukkavalli & Malavika Raman & Johannes C. Walter, 2022. "Cooperative assembly of p97 complexes involved in replication termination," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Shaun Scaramuzza & Rebecca M. Jones & Martina Muste Sadurni & Alicja Reynolds-Winczura & Divyasree Poovathumkadavil & Abigail Farrell & Toyoaki Natsume & Patricia Rojas & Cyntia Fernandez Cuesta & Mas, 2023. "TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Jessica D. Tischler & Hiroshi Tsuchida & Rosevalentine Bosire & Tommy T. Oda & Ana Park & Richard O. Adeyemi, 2024. "FLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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