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Chromatin retention of DNA damage sensors DDB2 and XPC through loss of p97 segregase causes genotoxicity

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  • Marjo-Riitta Puumalainen

    (Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse)

  • Davor Lessel

    (Institute of Human Genetics, University of Ulm)

  • Peter Rüthemann

    (Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse)

  • Nina Kaczmarek

    (Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse)

  • Karin Bachmann

    (Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse)

  • Kristijan Ramadan

    (Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse
    CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford)

  • Hanspeter Naegeli

    (Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse)

Abstract

DNA damage recognition subunits such as DDB2 and XPC protect the human skin from ultraviolet (UV) light-induced genome instability and cancer, as demonstrated by the devastating inherited syndrome xeroderma pigmentosum. Here we show that the beneficial DNA repair response triggered by these two genome caretakers critically depends on a dynamic spatiotemporal regulation of their homeostasis. The prolonged retention of DDB2 and XPC in chromatin, because of a failure to readily remove both recognition subunits by the ubiquitin-dependent p97/VCP/Cdc48 segregase complex, leads to impaired DNA excision repair of UV lesions. Surprisingly, the ensuing chromosomal aberrations in p97-deficient cells are alleviated by a concomitant downregulation of DDB2 or XPC. Also, genome instability resulting from an excess of DDB2 persisting in UV-irradiated cells is prevented by concurrent p97 overexpression. Our findings demonstrate that DNA damage sensors and repair initiators acquire unexpected genotoxic properties if not controlled by timely extraction from chromatin.

Suggested Citation

  • Marjo-Riitta Puumalainen & Davor Lessel & Peter Rüthemann & Nina Kaczmarek & Karin Bachmann & Kristijan Ramadan & Hanspeter Naegeli, 2014. "Chromatin retention of DNA damage sensors DDB2 and XPC through loss of p97 segregase causes genotoxicity," Nature Communications, Nature, vol. 5(1), pages 1-10, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4695
    DOI: 10.1038/ncomms4695
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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.

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