How ATR turns on: TopBP1 goes on ATRIP with ATR

Abstract

In this issue of Genes & Development, Mordes and colleagues (pp. 1478-1489) reveal intriguing mechanistic insights into activation of the ATR (ATM and Rad3-related) kinase critical for DNA damage resistance. They identify conserved regulatory domains within ATR and its binding partner ATRIP (ATR-interacting protein), which are contacted by the ATR activator TopBP1. These discoveries expand on our understanding of the regulation of other PIKK family members, which also contain these domains, and illustrate how functional diversity has been achieved among these kinases.

Figure 1.

How ATR is activated at stalled replication forks. (A) A schematic of ATR and its domains. (B) A model for ATR activation at a stalled replication fork. Upon encountering a replication-blocking lesion, denoted by the red X, loss of coordination between DNA polymerase and the MCM helicase generates ssDNA, which is coated by RPA. ATR–ATRIP and the RAD17/RFC2–5 complexes are independently recruited to ssDNA–RPA stretches and RAD17/RFC2–5 loads the RAD9–HUS1–RAD1 (9–1–1) clamp complex. TopBP1 binds RAD9 through a constitutively phosphorylated site on its C terminus. Several ATR-dependent phosphorylation events occur, including sites on RAD17, 9–1–1 clamp components, and TopBP1. Phosphorylated TopBP1 can bind surfaces on ATR and ATRIP, causing ATR to become activated and to phosphorylate its downstream effectors including Chk1.