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Kinase-dead ATR differs from ATR loss by limiting the dynamic exchange of ATR and RPA

Author

Listed:
  • Demis Menolfi

    (Columbia University)

  • Wenxia Jiang

    (Columbia University)

  • Brian J. Lee

    (Columbia University)

  • Tatiana Moiseeva

    (University of Pittsburgh School of Medicine, Hillman Cancer Center)

  • Zhengping Shao

    (Columbia University)

  • Verna Estes

    (Columbia University)

  • Mark G. Frattini

    (Columbia University)

  • Christopher J. Bakkenist

    (University of Pittsburgh School of Medicine, Hillman Cancer Center
    University of Pittsburgh School of Medicine, Hillman Cancer Center)

  • Shan Zha

    (Columbia University
    Columbia University)

Abstract

ATR kinase is activated by RPA-coated single-stranded DNA (ssDNA) to orchestrate DNA damage responses. Here we show that ATR inhibition differs from ATR loss. Mouse model expressing kinase-dead ATR (Atr+/KD), but not loss of ATR (Atr+/−), displays ssDNA-dependent defects at the non-homologous region of X-Y chromosomes during male meiosis leading to sterility, and at telomeres, rDNA, and fragile sites during mitosis leading to lymphocytopenia. Mechanistically, we find that ATR kinase activity is necessary for the rapid exchange of ATR at DNA-damage-sites, which in turn promotes CHK1-phosphorylation. ATR-KD, but not loss of ATR, traps a subset of ATR and RPA on chromatin, where RPA is hyper-phosphorylated by ATM/DNA-PKcs and prevents downstream repair. Consequently, Atr+/KD cells have shorter inter-origin distances and are vulnerable to induced fork collapses, genome instability and mitotic catastrophe. These results reveal mechanistic differences between ATR inhibition and ATR loss, with implications for ATR signaling and cancer therapy.

Suggested Citation

  • Demis Menolfi & Wenxia Jiang & Brian J. Lee & Tatiana Moiseeva & Zhengping Shao & Verna Estes & Mark G. Frattini & Christopher J. Bakkenist & Shan Zha, 2018. "Kinase-dead ATR differs from ATR loss by limiting the dynamic exchange of ATR and RPA," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07798-3
    DOI: 10.1038/s41467-018-07798-3
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