IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v6y2015i1d10.1038_ncomms9154.html
   My bibliography  Save this article

Kinase-independent role for CRAF-driving tumour radioresistance via CHK2

Author

Listed:
  • Sunil J. Advani

    (University of California, San Diego)

  • Maria Fernanda Camargo

    (University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA)

  • Laetitia Seguin

    (University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA)

  • Ainhoa Mielgo

    (University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA)

  • Sudarshan Anand

    (University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA)

  • Angel M. Hicks

    (University of California, San Diego)

  • Joseph Aguilera

    (University of California, San Diego)

  • Aleksandra Franovic

    (University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA)

  • Sara M. Weis

    (University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA)

  • David A. Cheresh

    (University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA)

Abstract

Although oncology therapy regimens commonly include radiation and genotoxic drugs, tumour cells typically develop resistance to these interventions. Here we report that treatment of tumours with ionizing radiation or genotoxic drugs drives p21-activated kinase 1 (PAK1)-mediated phosphorylation of CRAF on Serine 338 (pS338) triggering a kinase-independent mechanism of DNA repair and therapeutic resistance. CRAF pS338 recruits CHK2, a cell cycle checkpoint kinase involved in DNA repair, and promotes CHK2 phosphorylation/activation to enhance the tumour cell DNA damage response. Accordingly, a phospho-mimetic mutant of CRAF (S338D) is sufficient to induce the CRAF/CHK2 association enhancing tumour radioresistance, while an allosteric CRAF inhibitor sensitizes tumour cells to ionizing radiation or genotoxic drugs. Our findings establish a role for CRAF in the DNA damage response that is independent from its canonical function as a kinase.

Suggested Citation

  • Sunil J. Advani & Maria Fernanda Camargo & Laetitia Seguin & Ainhoa Mielgo & Sudarshan Anand & Angel M. Hicks & Joseph Aguilera & Aleksandra Franovic & Sara M. Weis & David A. Cheresh, 2015. "Kinase-independent role for CRAF-driving tumour radioresistance via CHK2," Nature Communications, Nature, vol. 6(1), pages 1-8, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9154
    DOI: 10.1038/ncomms9154
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms9154
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms9154?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Johanna Zerbib & Marica Rosaria Ippolito & Yonatan Eliezer & Giuseppina Feudis & Eli Reuveni & Anouk Savir Kadmon & Sara Martin & Sonia Viganò & Gil Leor & James Berstler & Julia Muenzner & Michael Mü, 2024. "Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9154. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.