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p53-mediated apoptosis and genomic instability syndromes
Breast Cancer Research volume 2, Article number: S.20 (2000)
The eukaryote genome is constantly facing the threat of damage from exogenous and endogenous mutagens. Mammalian cells, therefore, have evolved an intricate network of defenses to maintain genomic stability, eg, cell-cycle checkpoints, DNA repair, and apoptosis. Defects in these processes can result in a mutator phenotype associated with tumorigenesis, as exemplified by a number of familial cancer-prone disorders, including xeroderma pigmentosum (XP), Bloom syndrome (BS), ataxia telangiectasia (AT), Werner syndrome (WS) and Li-Fraumeni syndrome (LFS). p53 is at the crossroads of these pathways, and provides a biological basis for p53 being a prime target of somatic mutations in human cancers. We are investigating the molecular mechanisms related to these pathways. For example, p53 binds to the basal transcription and nucleotide-excision repair complex, TFIIH, through interaction with two DNA helicases, XPB and XPD, and cells with p53 inactivation have a reduced DNA repair activity. Using a genetic approach, we also showed that XPB and XPD contribute to p53-mediated apoptosis. These data indicate that p53 may modulate either DNA repair or apoptosis by binding to and regulating the activity of the TFIIH-associated DNA helicases. We are also investigating the physical and functional interactions between p53 and other DNA helicases, including WRN and BLM. Our data are consistent with the hypothesis that WRN and BLM contribute to the removal of blocks in DNA replication due to either errors during DNA metabolism or carcinogen-induced DNA damage. WS or BS fibroblasts have an attenuated p53-mediated apoptotic response, and this deficiency can be rescued by the expression of wild-type WRN or BLM, respectively. These data further support the hypothesis that p53 can induce apoptosis through the modulation of specific DExH-containing DNA helicases, and may have implications for the cancer predisposition observed in these genomic instability diseases.
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Spillare, E., Wang, X., Linke, S. et al. p53-mediated apoptosis and genomic instability syndromes. Breast Cancer Res 2 (Suppl 1), S.20 (2000). https://doi.org/10.1186/bcr139