FIGURE 19-29 The DNA damage response system. The protein kinases ATM and ATR are activated by damaged DNA. ATR responds to a variety of DNA damage—most likely to the single-stranded DNA that exists either as a result of the damage itself or as a result of repair. ATM is specifically activated by double-strand breaks. Because double-strand breaks are converted into single-stranded DNA as a part of the repair process, they also, albeit indirectly (as depicted by a dashed line), activate ATR. ATM and ATR, once activated by DNA damage, activate another pair of related protein kinases, Chk1 and Chk2. These kinases then induce the DNA repair machinery and cause cell cycle arrest by inhibiting Cdc25. In metazoan cells, Chk1 and Chk2 also activate the transcription factor p53, which induces cell cycle arrest by inducing transcription of the CKI p21. When the DNA damage is severe, p53 induces apoptosis.