Atr Conditional Knockout mouse models

Distinct from ATM in trigger and kinetics, Atr is the mouse ortholog of human ATR and encodes the PIKK that responds to RPA coated single stranded DNA at stalled forks and resected ends, recruited through its obligate partner ATRIP and activated allosterically by TOPBP1 or ETAA1 to phosphorylate CHK1 at S317 and S345, RPA32 and the 9-1-1 clamp, thereby suppressing origin firing, stabilizing forks and enforcing the replication checkpoint. Complete loss is cell lethal and embryonic lethal, so hypomorphic Seckel syndrome knockins and conditional floxed alleles with inducible Cre are the only workable designs for studying replication stress in vivo. Acute conditional deletion in adult tissue produces stem cell attrition and progeroid features, giving a mechanistic readout for ATR inhibitor toxicity. Chek1 sits immediately downstream and is not redundant, so do not expect ATM to substitute. Select hypomorphs for chronic replication stress biology and conditional nulls for acute dependency and inhibitor mechanism-of-action work in ATM deficient or oncogene driven tumors.

Tissue restricted knockout of Atr keeps wild type function everywhere else. Breeding is often more robust, and the setup mirrors patient biology where mutations arise in a subset of cells.