DNA Damage Response (DDR) pathways in normal and malignant cells. In normal cells, different types of genotoxic stress (e.g., DNA double-strand breaks) or DNA replication stress elicit DDR as part of the self-defense system. This involves the activation (via phosphorylation) of “sensor” kinases, ATM and ATR, which in turn activate Chk2 and Chk1 checkpoint kinases, respectively, all leading to phosphorylation of histone H2AX at the sites of DNA damage. These events invoke multiple downstream pathways which, depending on the extent of DNA damage, induce either cell cycle arrest (permitting DNA repair) or apoptosis (in case of irreparable DNA damage). Thus, cell cycle arrest can result from Chk1/2-dependent activating phosphorylation of p53 tumor suppressor gene or inactivating phosphorylation of Cdc25 family phosphatases which lead, respectively, to an upregulation of cyclin-dependent kinase inhibitor p21Waf1, or inhibition of CDK2 activity by rendering it in an inactive (phosphorylated) state. Alternatively, Chk1/2-dependent activation of p53 can induce apoptosis via upregulation and activation of a subset of pro-apoptotic proteins. A similar apoptotic effect may result from ATM-dependent phosphorylation of the nonreceptor tyrosine kinase c-Abl, which phosphorylates and activates the p53-related protein p73,, leading to induction of pro-apoptotic genes in a manner that overlaps with the effect of p53 (reviewed in ref. ). Interestingly, besides promoting cell cycle arrest, DDR-triggered inhibition of CDK2 may also contribute to the induction of pro-apoptotic genes by rendering the transcription factor FOXO-1 in its active (unphosphorylated) state. In accordance with the data obtained by Oka et al. colon tumorigenesis is associated with a gradual activation of the upstream DDR elements (ATM, Chk2 and H2AX) but, paradoxically, this does not result in an increased apoptosis induction, suggesting that malignant transformation may result in impairments of the DDR pathways downstream from Chk1/2 and the ATM-cAbl pathway (indicated by red crosses).
