Sequence of events in ATM→ ATR dependent signaling of DSBs in S/G2 cells. (1) Recuitment of the MRN complex to the DSB. (2) Recuitment/activation of ATM to DSBs. (3) ATM dependent stimulation of the Mre11-dependent 5' to 3' nuclease activity. (4) Generation of ssDNA. (5) Recruitment of RPA to the generated ssDNA. (6) Recruitment of the ATRIP/ATR complex to ssDNA-bound RPA. (7) ATR dependent activation of Chk1. (8) Inhibition of the specific CDK activity responsible for S and/or G2/M progression; in other words, execution of the checkpoint. (9) Control of the ssDNA/RPA/ATR pathway by CDK activity. The numbers followed by an asterisk (3,4 and 9) point to the less understood concepts of the model: (3)* How does ATM stimulate Mre11 nuclease activity? (4)* To what extent is Mre11 nuclease activity responsible for the ssDNA generation in response to IR-induced DSBs? And, most importantly; (9)* how does CDK activity "preactivate" the ATR/Chk1 pathway?