Radiosensitivity and the Cell Cycle - Chapter 4 jtl
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Radiosensitivity and the Cell Cycle - Chapter 4 jtl
- 1. Chapter 4: Radiosensitivity and Cell Age in the Mitotic Cycle JTL
- 3. The Cell Cycle G1 = 1st Gap S = Synthesis G2 = 2nd Gap M = Mitosis
- 20. OER
- 32. Labelling Index = (Ts/Tc) Ts = LI(Tc/ ) Ts=0.2(72hrs/0.7)=20.6 hrs
- 34. Total Tc = 20hrs, Ts=5hrs so roughly 1/4 of dividing cells are in S phase. Growth Fraction is 0.5 so about half of cells are dividing so 1/8 of all cells are in S phase. 1/8 x (2 x 10 7 cells)= 2.5 x 10 6
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- a , Ionizing radiation activates the kinase ATM, which in turn activates the kinase Chk2 . b , This step appears to affect progression from G1 to the S phase, through phosphorylation (represented by a circled 'P') and stabilization of the p53 protein, which itself enhances the expression of the cell-cycle inhibitor p21 . c , Activation of Chk2 by ATM also affects progression through the S phase itself, by the phosphorylation of Cdc25A. This protein is more likely to be degraded when phosphorylated . (When unphosphorylated, Cdc25A removes a phosphate group from Cdk2, enabling the initiation of DNA replication, that is, S phase.) d , Nbs1 is also phosphorylated by ATM and is also involved in the ionizing-radiation-induced inhibition of S-phase progression , although it is not known how it ties in to the pathway described by Falck et al. e , The targets of ATM that control progression from G2 into mitosis (M phase) have not been described.
- Signal transduction pathways are activated by either ataxia telangiectasia mutated (ATM) or ataxia telangiectasia and RAD3-related (ATR). ATM responds to double strand breaks (DSBs), and evidence suggests an activating role for the NBS1–MRE11–RAD50 (MRN) complex 70 . ATR responds to single stranded regions of DNA, and requires ATR-interacting protein (ATRIP), RPA 71 , the RAD17–RFC2-5 complex, a complex of RAD9–HUS1–RAD1 (the 9–1–1 complex) 72 , TOPBP1 and claspin. The signalling pathways involve the mediator proteins (MDC1, 53BP1, the MRN complex and BRCA1), which amplify the signal, transducer kinases (CHK1 and CHK2) and effector proteins 17 . ATM and ATR show considerable overlap in their phosphorylation substrates but specificity also exists, with CHK1 and CHK2 being specific substrates of ATR and ATM, respectively. Two ATM-dependent G1/S checkpoints have been described. ATM activation by DSBs in G1 leads to CHK2 phosphorylation and subsequent phosphorylation of the phosphatase CDC25A. This increases the ubiquitylation and proteolytic degradation of CDC25A and prevents activating dephosphorylation of CDK2 at Thr14 and Tyr15 59, 73, 74 . As this pathway operates through post-translational modifications, initiation of the G1/S checkpoint occurs soon after damage induction. A second mechanism involves the tumour suppressor p53, which is activated and stabilized by ATM, either directly or indirectly through CHK2, and serves as a transcription factor for the cyclin-dependent kinase (CDK) inhibitor p21 (Refs 49 , 58 , 59 ). This pathway depends on the transcription of p21 and is therefore delayed after ionizing radiation (IR), suggesting that its role lies in the maintenance of the G1/S checkpoint 49, 57, 59, 75 . Collapsed or stalled replication forks in S phase activate ATR, leading to the phosphorylation of CHK1 and the subsequent phosphorylation and proteolysis of CDC25A 59 . This prevents initiation of new replication origins and slows down replication. A second branch of this intra-S phase checkpoint involves the MRN complex, BRCA1, FANCD2 and SMC1 76 (not shown in figure). DSBs in G2 can directly activate ATM, and indirectly, via ATM-dependent strand resection, can lead to ATR activation 64 . Similar to the rapid activation of the G1/S and intra-S phase checkpoints, the G2/M checkpoint is initiated by the phosphorylation of checkpoint kinases (CHK1 and CHK2) and phosphatases (probably CDC25C). This prevents dephosporylation of CDK1–cyclin B, which is required for progression into mitosis 23, 59 . Although p53 has an essential role in p21-dependent G1/S arrest , it promotes but is non-essential for the G2/M checkpoint . Roles include an affect on the maintenance of checkpoint arrest and on CDK1–cyclin B activity through transcriptional activation and regulation of GADD45 and 14-3-3
- Checkpoint adaptation may lead to IR-induced genomic instability. Most of the cells with unrepairable DNA lesions will die following adaptation to the IR-induced G2 checkpoint. However, some cells might survive and proliferate with DNA lesions, making them prone to development of genomic instability and cancer. Cyclin B/Cdk1 activity is regulated by multiple factors including transcription of cyclin B and the extent of inhibitory phosphorylations on Cdk1, the latter being controlled by Plk1 and Chk1. Similar to adaptation in aphidicolin-treated Xenopus extracts, Plk1 may also control Chk1-inactivation during checkpoint adaptation in human cells. DOSE EFFECT: Adaptation likely occurs when the cyclin B/Cdk1 activity accumulates to a level sufficient to trigger mitotic entry. Adaptation may therefore occur owing to accumulation of cyclin B protein level, inactivation of Chk1, accumulation of Plk1 activity, and/or other factors that control cyclin B/Cdk1 activity.
- Defects in repair and checkpoint arrest significantly affect cell survival following ionizing radiation, but confer only a small (repair defect) or modest (checkpoint loss) increase in chromosome breakage. However, the combined defect results in high levels of chromosome breakage and, by inference, increased chromosome rearrangements and tumour cell develop-ment. DSB, double strand break.