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RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation

Author

Listed:
  • Kiran Kumar Naidu Guturi

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Miyuki Bohgaki

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Toshiyuki Bohgaki

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Tharan Srikumar

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Deborah Ng

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Ramya Kumareswaran

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Samah El Ghamrasni

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Justin Jeon

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Parasvi Patel

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Mohamed Saad Eldin

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Rob Bristow

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Peter Cheung

    (York University)

  • Grant S. Stewart

    (School of Cancer Sciences, University of Birmingham)

  • Brian Raught

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Anne Hakem

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

  • Razqallah Hakem

    (Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto)

Abstract

Topoisomerase IIα (TOP2α) is essential for chromosomal condensation and segregation, as well as genomic integrity. Here we report that RNF168, an E3 ligase mutated in the human RIDDLE syndrome, interacts with TOP2α and mediates its ubiquitylation. RNF168 deficiency impairs decatenation activity of TOP2α and promotes mitotic abnormalities and defective chromosomal segregation. Our data also indicate that RNF168 deficiency, including in human breast cancer cell lines, confers resistance to the anti-cancer drug and TOP2 inhibitor etoposide. We also identify USP10 as a deubiquitylase that negatively regulates TOP2α ubiquitylation and restrains its chromatin association. These findings provide a mechanistic link between the RNF168/USP10 axis and TOP2α ubiquitylation and function, and suggest a role for RNF168 in the response to anti-cancer chemotherapeutics that target TOP2.

Suggested Citation

  • Kiran Kumar Naidu Guturi & Miyuki Bohgaki & Toshiyuki Bohgaki & Tharan Srikumar & Deborah Ng & Ramya Kumareswaran & Samah El Ghamrasni & Justin Jeon & Parasvi Patel & Mohamed Saad Eldin & Rob Bristow , 2016. "RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12638
    DOI: 10.1038/ncomms12638
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