Conclusions

The telomerase-deficient mouse has been invaluable in providing insights into basic questions pertaining to consequences of telomere dysfunction during aging and cancer in the context of the mammalian organism. Studies in this mouse model have demonstrated that cellular responses to telomere dysfunction are fundamentally conserved in both humans and mice, and that p53 plays a key role in sensing and mediating responses to dysfunctional telomeres Figure 4.1. Telomere dysfunction leads to genomic instability and activation of the DNA damage response checkpoints. In the setting of an intact p53 pathway, telomere dysfunction in late-generation mTerc-/- mice activates p53, leading to tumor suppression as a result of increased cellular senescence (Cosme-Blanco et al. 2007). However, inappropriate activation of p53 also promotes premature organismal aging (Rudolph et al. 1999, Herrera et al. 2000). On the other hand, loss of p53 function cooperates with dysfunctional telomeres to promote carcinogenesis at the expense of premature aging (Chin et al. 1999). The conclusion suggested by these contrasting results argue that

S-phase

NHEJ

G2 phase

G2 phase

NHEJ

ATM-P

ATM-P

Chk2-P

p53-P

0 0

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