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

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

SUBMITTER: Menolfi D 

PROVIDER: S-EPMC6297235 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature