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

Demis Menolfi, Wenxia Jiang, Brian J. Lee, Tatiana Moiseeva, Zhengping Shao, Verna Estes, Mark G. Frattini, Christopher J. Bakkenist and Shan Zha ()
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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
Shan Zha: Columbia University

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07798-3

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