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CDK1 phosphorylates WRN at collapsed replication forks

Author

Listed:
  • Valentina Palermo

    (Section of Experimental and Computational Carcinogenesis, Istituto Superiore di Sanità)

  • Sara Rinalducci

    (Proteomics Lab, Università della Tuscia)

  • Massimo Sanchez

    (Section of Gene and Cell Therapy, Istituto Superiore di Sanità)

  • Francesca Grillini

    (Section of Experimental and Computational Carcinogenesis, Istituto Superiore di Sanità)

  • Joshua A. Sommers

    (Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center)

  • Robert M. Brosh

    (Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center)

  • Lello Zolla

    (Proteomics Lab, Università della Tuscia)

  • Annapaola Franchitto

    (Section of Molecular Epidemiology, Istituto Superiore di Sanità)

  • Pietro Pichierri

    (Section of Experimental and Computational Carcinogenesis, Istituto Superiore di Sanità)

Abstract

Regulation of end-processing is critical for accurate repair and to switch between homologous recombination (HR) and non-homologous end joining (NHEJ). End resection is a two-stage process but very little is known about regulation of the long-range resection, especially in humans. WRN participates in one of the two alternative long-range resection pathways mediated by DNA2 or EXO1. Here we demonstrate that phosphorylation of WRN by CDK1 is essential to perform DNA2-dependent end resection at replication-related DSBs, promoting HR, replication recovery and chromosome stability. Mechanistically, S1133 phosphorylation of WRN is dispensable for relocalization in foci but is involved in the interaction with the MRE11 complex. Loss of WRN phosphorylation negatively affects MRE11 foci formation and acts in a dominant negative manner to prevent long-range resection altogether, thereby licensing NHEJ at collapsed forks. Collectively, we unveil a CDK1-dependent regulation of the WRN-DNA2-mediated resection and identify an undescribed function of WRN as a DSB repair pathway switch.

Suggested Citation

  • Valentina Palermo & Sara Rinalducci & Massimo Sanchez & Francesca Grillini & Joshua A. Sommers & Robert M. Brosh & Lello Zolla & Annapaola Franchitto & Pietro Pichierri, 2016. "CDK1 phosphorylates WRN at collapsed replication forks," Nature Communications, Nature, vol. 7(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12880
    DOI: 10.1038/ncomms12880
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    Cited by:

    1. Arindam Datta & Kajal Biswas & Joshua A. Sommers & Haley Thompson & Sanket Awate & Claudia M. Nicolae & Tanay Thakar & George-Lucian Moldovan & Robert H. Shoemaker & Shyam K. Sharan & Robert M. Brosh, 2021. "WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-22, December.

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