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Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice

Author

Listed:
  • Nozomi Tomimatsu

    (University of Texas Southwestern Medical Center)

  • Bipasha Mukherjee

    (University of Texas Southwestern Medical Center)

  • Molly Catherine Hardebeck

    (University of Texas Southwestern Medical Center)

  • Mariya Ilcheva

    (University of Texas Southwestern Medical Center)

  • Cristel Vanessa Camacho

    (University of Texas Southwestern Medical Center
    Present address: Department of Genetics, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA)

  • Janelle Louise Harris

    (Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute)

  • Matthew Porteus

    (Deparment of Pediatrics, Stanford University)

  • Bertrand Llorente

    (CRCM, Inserm, U1068; Aix-Marseille Université, UM 105; CNRS, UMR7258
    Institut Paoli-Calmettes)

  • Kum Kum Khanna

    (Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute)

  • Sandeep Burma

    (University of Texas Southwestern Medical Center)

Abstract

Resection of DNA double-strand breaks (DSBs) is a pivotal step during which the choice between NHEJ and HR DNA repair pathways is made. Although CDKs are known to control initiation of resection, their role in regulating long-range resection remains elusive. Here we show that CDKs 1/2 phosphorylate the long-range resection nuclease EXO1 at four C-terminal S/TP sites during S/G2 phases of the cell cycle. Impairment of EXO1 phosphorylation attenuates resection, chromosomal integrity, cell survival and HR, but augments NHEJ upon DNA damage. In contrast, cells expressing phospho-mimic EXO1 are proficient in resection even after CDK inhibition and favour HR over NHEJ. Mutation of cyclin-binding sites on EXO1 attenuates CDK binding and EXO1 phosphorylation, causing a resection defect that can be rescued by phospho-mimic mutations. Mechanistically, phosphorylation of EXO1 augments its recruitment to DNA breaks possibly via interactions with BRCA1. In summary, phosphorylation of EXO1 by CDKs is a novel mechanism regulating repair pathway choice.

Suggested Citation

  • Nozomi Tomimatsu & Bipasha Mukherjee & Molly Catherine Hardebeck & Mariya Ilcheva & Cristel Vanessa Camacho & Janelle Louise Harris & Matthew Porteus & Bertrand Llorente & Kum Kum Khanna & Sandeep Bur, 2014. "Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4561
    DOI: 10.1038/ncomms4561
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    Cited by:

    1. Lorenzo Galanti & Martina Peritore & Robert Gnügge & Elda Cannavo & Johannes Heipke & Maria Dilia Palumbieri & Barbara Steigenberger & Lorraine S. Symington & Petr Cejka & Boris Pfander, 2024. "Dbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Adrián Campos & Facundo Ramos & Lydia Iglesias & Celia Delgado & Eva Merino & Antonio Esperilla-Muñoz & Jaime Correa-Bordes & Andrés Clemente-Blanco, 2023. "Cdc14 phosphatase counteracts Cdk-dependent Dna2 phosphorylation to inhibit resection during recombinational DNA repair," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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