Figure 1. ATM/ATR-dependent cell cycle arrest or apoptosis in response to UVR.

(A.) UVR-induced DSB trigger autophosphorylation of ATM at Ser³⁶⁷, Ser¹⁸⁹³, Ser¹⁹⁸¹ and Ser²⁹⁹⁶. The active ATM monomer phosphorylates CHK2 at Thr⁶⁸, which leads to inhibition of cell cycle progression through an inhibitory phosphorylation of CDC25 at Ser²¹⁶. ATM can either directly phosphorylates p53 at Ser⁹, Ser¹⁵, and Ser⁴⁶ or indirectly regulate p53 through phosphorylation (at Ser³⁹⁴) and inhibition of MDM2. Both of these events lead to cell cycle arrest or, with prolonged ATM activation, apoptosis. ATM can also phosphorylate CHK2 (at Ser³⁶⁴) and the transcription factor E2F1 (at Ser³¹), both of which ultimately lead to apoptosis. (B.) UVR-induced SSB lead to ATR activation and increased p53 stability through an inhibitory phosphorylation of MDM2 at Ser⁴⁰⁷. Direct phosphorylation (at Ser¹⁹) of the E3 ubiquitin ligase SIAH1 by ATR results in SIAH1 inhibition, which allows HIPK2 to activate p53. SIAH1 inhibition can also occur through ATR-dependent phosphorylation of ATM at Ser¹⁹⁸¹. Phosphorylation of CHK1 at Ser³⁴⁵ by ATR can lead to cell cycle arrest by several routes: CHK1 can directly phosphorylate CDC25 or indirectly inhibit CDC25 through NEK11 or PLK-1. Excessive DNA damage caused by high-dose UVB can also lead to promotion of apoptosis through p21 inhibition (see text for details). Solid lines indicate UVR-induced events, while dotted lines represent outcomes in the absence of UVR.