ATR
ATR guards the genome against replication stress. It is recruited by its partner ATRIP to RPA-coated single-stranded DNA and is fully activated at primed junctions through TOPBP1 and the 9-1-1 clamp. Once engaged, ATR phosphorylates Chk1 and hundreds of other substrates to slow origin firing, stabilize stalled replication forks and coordinate repair, and it also restrains R-loop accumulation and fragile-site instability. Unlike ATM, which senses double-strand breaks, ATR responds mainly to single-stranded DNA; hypomorphic ATR mutations cause the microcephalic primordial dwarfism disorder Seckel syndrome. Recombinant ATR is essential for reconstituting replication-stress kinase assays and screening ATR inhibitors.
