Kinase-dead ATR differs from ATR loss by limiting the dynamic exchange of ATR and RPA.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30559436.
- Also identified by DOI 10.1038/s41467-018-07798-3 and PMC identifier 6297235.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>+/KD</sup>), but not loss of ATR (Atr<sup>+/-</sup>), 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<sup>+/KD</sup> 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.
Medical subject headings
- DNA Damage
- DNA Repair
- DNA, Single-Stranded