ReviewConstitutively active DNA damage checkpoint pathways as the driving force for the high frequency of p53 mutations in human cancer
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p53 as the most frequently inactivated gene in human cancer
p53 has been one of the best studied molecules in human cancer claiming such distinctions as “molecule of the year” in 1993, a workshop series dedicated exclusively to it and more than 14,000 publications in the biomedical literature with the keyword “p53” in their title [1], [2]. The interest in p53 stems from the high frequency of p53 inactivation in human cancer. About half of all human tumors have a mutation in the p53 gene, which encodes the p53 protein, that inactivates its function and a
Hypotheses to explain the high frequency of p53 inactivation in human cancer
Several hypotheses have been proposed to explain the high frequency of p53 inactivation in human cancer. A hypothesis that has caught a lot of attention is the “guardian of the genome” hypothesis [15]. As its name indicates, p53 is proposed to guard the genome from accumulation of oncogenic mutations. The strongest evidence in support of this hypothesis comes from analysis of p53 knockout mice [7]. Since these mice develop tumors with 100% penetrance, the absence of p53 function must be
A hypothesis to explain the high frequency of p53 inactivation in human cancer based on the function of p53 as a DNA damage checkpoint protein
A large number of functions have been attributed to the p53 protein. Of all these functions, the role of p53 in the DNA damage response [23] is probably the best understood, as evidenced by the elucidation of specific pathways by which DNA damage leads to p53 activation (Fig. 1). In response to DNA DSBs several proteins, including 53BP1, NFBD1/MDC1 and the Nbs1–Mre11–Rad50 complex accumulate at the sites of DNA DSBs, a process required for activation of the ATM protein kinase, which in turn
Evidence for constitutive activation of the DNA DSB checkpoint in human cancer
As the DNA damage checkpoint pathways are being elucidated, markers are becoming available to assay whether these pathways are active or inactive in human cancer cell lines and tumors. The Chk2 kinase is activated by ATM in response to DNA DSBs (Fig. 1) and activation involves phosphorylation of Thr68 of Chk2 by ATM [37]. This phosphorylation event can be monitored with a phosphospecific antibody, which is suitable for both Western blot analysis and immunohistochemistry. In a small panel of
DNA DSBs in human tumors and experimentally transformed cells
The highly aberrant karyotype of most cancer cells de facto implies that DNA DSBs must have occurred at some point during cancer development. It is generally thought that DSBs occur during “crisis”, when telomeres become eroded and chromosomal ends are recognized by the cell as DNA DSBs [39], [40]. Cancer cells emerge from crisis with chromosomal rearrangements arising from aberrant DNA repair and with the ability to maintain their telomeres most often by regaining expression of telomerase [41]
Activation of the DNA damage checkpoint as a survival mechanism for cancer cells with DNA DSBs
Irrespective of the mechanism by which cancer cells develop DNA DSBs, the presence of breaks constitutes a threat to cell survival. DNA DSBs in cells entering mitosis will lead to chromosome fragments lacking centrosomes; such fragments cannot be properly segregated between the two daughter cells resulting in loss of genetic material and cell death. Activation of the DNA damage checkpoint is probably critical to preventing entry of cancer cells with DNA DSBs into mitosis. Thus, the genes
Therapeutic implications
The concept that at least a subset of tumors constantly form DNA DSBs suggests that these cells will be vulnerable to agents that compromise the DNA damage checkpoint and DNA repair pathways. In fact, current cancer therapy uses agents that block DNA replication or directly induce DNA damage. These agents may be effective, in part, because they further challenge the ability of cancer cells to complete DNA replication and repair the DNA DSBs that arise as a byproduct of their transformed
Acknowledgements
It was impossible within the confines of this review to present all points of view relevant to this topic, as well as to cite all the relevant literature. Work from my laboratory presented in this review was supported by grant CA76367 from the National Institutes of Health.
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