Defective DNA damage responses in MCL. DNA damage activates the kinases ATM and ATR, together with p53 and p14/ARF, which can induce cell-cycle arrest, DNA repair, or apoptosis. The E3-ubiquitin ligase MDM2 that targets p53 for proteasomal degradation is inhibited by ARF, which in turn is inhibited by BMI1. CHK1 and CHK2, activated by ATR and ATM, respectively, phosphorylate key substrates (p53, CDC25A, CDC25B), leading to cell-cycle arrest. Several steps in this DNA damage response are altered in MCL: blue symbols (Δ) indicate molecules inactivated or down-regulated; red symbols, molecules activated or overexpressed. Illustration by Paulette Dennis.