FIGURE 1-11 Network of protein kinases activated by DNA DSBs. ATM is the primary kinase that phosphorylates downstream kinases. The specific activity of ATM is increased after introduction of DSBs in DNA through ionizing radiation or other means; this then activates other proteins by phosphorylation (denoted by amino acid symbol and number) and in a cell cycle-specific manner. G1phase: Activated ATM (ATM*) directly phosphorylates three proteins involved in controlling p53 functions or levels—p53 (serine 15), CHK2 (threonine 68), and MDM2 (serine 395). CHK2 kinase may also be activated by ATM and in turn phosphorylate p53 on serine 20. This phosphorylation event and the phosphorylation of MDM2 seem to inhibit binding of MDM2 to p53 and should result in an increase in p53 protein. The increased p53 protein transcriptionally induces p21, which inhibits CDK2-cyclin E and causes arrest in the G1 phase of the cycle. S phase: Activated ATM also phosphorylates NBS1 (serine 343), and this phosphorylation event is required for the ionizing radiation-induced S-phase arrest. NBS1 exists in a complex with MRE11, RAD50, and BRCA1. The potential role of these proteins in S-phase arrest remains to be clarified; CHK2 may also be involved in this pathway, after activation by ATM, through phosphorylation of BRCA1 or NBS1. G2 phase: Details of the downstream targets of ATM at the G2 checkpoint have not been determined. CHK2 and CHK1 may be targets for ATM and ATR in the G2-M checkpoint pathway, respectively. CDC25C and 14-3-3 have been implicated in regulation of CDC2 kinase and progression through G2. Dashed arrows and question marks represent possible signaling steps; solid arrows represent reported phosphorylation events. SOURCE: Reproduced with permission from Kastan and Lim (2000).

major difference from microorganisms is that mammalian enzymes are constitutively expressed. Thus, there are no transcription control or mammalian counterparts of soxR, ada, and lex. This situation presumably reflects the much greater constancy of cellular environment in complex multi-cellular organisms. Therefore, the work on inducible DNA repair in bacteria offers no direct guidelines for the relative resistance of human cells repeatedly exposed to DNA-damaging agents.

Many reports have appeared about adaptive responses involving increased resistance or hypersensitivity in mammalian cells in response to single or multiple doses of ionizing radiation (adaptive effects). There are also reports that the effects of radiation on single cells can influence the response of adjacent nonirradiated cells (bystander effect). These reports are discussed specifically in Chapter 2, but this chapter describes the general stress response and signal transduction pathways that are known to occur after exposure to radiation.

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