ATR: an essential regulator of genome integrity

Abstract

Ataxia-telangiectasia mutated (ATM) and RAD3-related (ATR) is a member of the phosphoinositide 3-kinase (PI3K)-related family of protein kinases, which includes ATM, that regulates DNA-damage responses to maintain genome integrity. A common DNA structure — single-stranded DNA (ssDNA) with a 5′ double-stranded primer junction — is responsible in most instances for ATR activation. ATR binds to a protein cofactor, ATR-interacting protein (ATRIP), that regulates ATR localization and activation. Topoisomerase-binding protein-1 (TOPBP1) directly activates ATR–ATRIP complexes. Its recruitment to DNA lesions is promoted by the 9-1-1 checkpoint clamp. ATR signals to regulate DNA replication, cell-cycle transitions and DNA repair through the phosphorylation of hundreds of substrates, including checkpoint kinase-1 (CHK1) and the minichromosome maintenance (MCM) helicase complex. ATM and ATR have overlapping but non-redundant functions in the DNA-damage response. Crosstalk between these pathways often occurs as a consequence of interconversion of the activating DNA lesions. ATR is essential for the survival of most replicating cells, perhaps because of the ubiquitous presence of DNA lesions and replication stress.