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Synergistic Interaction of Rnf8 and p53 in the Protection against Genomic Instability and Tumorigenesis
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نویسنده
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halaby m.-j. ,hakem a. ,li l. ,el ghamrasni s. ,venkatesan s. ,hande p.m. ,sanchez o. ,hakem r.
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منبع
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plos genetics - 2013 - دوره : 9 - شماره : 1
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چکیده
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Rnf8 is an e3 ubiquitin ligase that plays a key role in the dna damage response as well as in the maintenance of telomeres and chromatin remodeling. rnf8-/- mice exhibit developmental defects and increased susceptibility to tumorigenesis. we observed that levels of p53,a central regulator of the cellular response to dna damage,increased in rnf8-/- mice in a tissue- and cell type-specific manner. to investigate the role of the p53-pathway inactivation on the phenotype observed in rnf8-/- mice,we have generated rnf8-/-p53-/- mice. double-knockout mice showed similar growth retardation defects and impaired class switch recombination compared to rnf8-/- mice. in contrast,loss of p53 fully rescued the increased apoptosis and reduced number of thymocytes and splenocytes in rnf8-/- mice. similarly,the senescence phenotype of rnf8-/- mouse embryonic fibroblasts was rescued in p53 null background. rnf8-/-p53-/- cells displayed defective cell cycle checkpoints and dna double-strand break repair. in addition,rnf8-/-p53-/- mice had increased levels of genomic instability and a remarkably elevated tumor incidence compared to either rnf8-/- or p53-/- mice. altogether,the data in this study highlight the importance of p53-pathway activation upon loss of rnf8,suggesting that rnf8 and p53 functionally interact to protect against genomic instability and tumorigenesis. © 2013 halaby et al.
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آدرس
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department of medical biophysics,university of toronto and ontario cancer institute,university health network,toronto,on, Canada, department of medical biophysics,university of toronto and ontario cancer institute,university health network,toronto,on, Canada, department of medical biophysics,university of toronto and ontario cancer institute,university health network,toronto,on, Canada, department of medical biophysics,university of toronto and ontario cancer institute,university health network,toronto,on, Canada, department of physiology,yong loo lin school of medicine and tembusu college,national university of singapore,singapore, Singapore, department of physiology,yong loo lin school of medicine and tembusu college,national university of singapore,singapore, Singapore, university of ontario institute of technology,oshawa,on, Canada, department of medical biophysics,university of toronto and ontario cancer institute,university health network,toronto,on, Canada
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Authors
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