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Fig. 2. Model for replication-dependent ATR activation. When a polymerase encounters a lesion (shown here on the leading strand), the polymerase is slowed while the minichromosome maintenance (MCM) helicase continues to unwind the duplex DNA. This leads to accumulation of single-stranded DNA on the leading and/or lagging strand and recruitment of RPA and polymerase {alpha}. The ATR-ATRIP complex and the 9-1-1 complex are then recruited to the ssDNA. Phosphorylation and activation of Chk1 follows and is mediated by claspin and/or additional mediator proteins.