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RAP80 is critical in maintaining genomic stability and suppressing tumor development.

Cancer research | Oct 1, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22896338

The ubiquitin interaction motif-containing protein RAP80 was recently found to play a key role in DNA damage response (DDR) signaling by facilitating the translocation of several DDR mediators, including BRCA1, to ionizing irradiation (IR)-induced foci. In this study, we examine the effect of the loss of RAP80 on genomic stability and the susceptibility to cancer development in RAP80 null (RAP80(-/-)) mice. RAP80(-/-) mice are viable and did not exhibit any apparent developmental defects. Mouse embryonic fibroblasts (MEF) derived from RAP80(-/-) mice underwent premature senescence compared with wild-type (WT) MEFs, were more sensitive to IR, and exhibited a higher level of spontaneous and IR-induced genomic instability. RAP80(-/-) thymocytes were more sensitive to IR-induced cell death than WT thymocytes. RAP80(-/-) mice were more susceptible to spontaneous lymphoma development and the development of 7,12-dimethylbenz(a)anthracene-induced mammary gland tumors. Moreover, the loss of RAP80 accelerated tumor formation in both p53(-/-) and p53(+/-) mice. Our data indicate that RAP80-deficiency promotes genomic instability and causes an increase in cancer risk consistent with the concept that RAP80 exhibits a tumor suppressor function.

Pubmed ID: 22896338 RIS Download

Mesh terms: Animals | Benz(a)Anthracenes | Cell Aging | Cell Cycle Proteins | Cells, Cultured | Embryo, Mammalian | Female | Fibroblasts | Gene Expression Regulation, Neoplastic | Genomic Instability | Kaplan-Meier Estimate | Lymphoma | Male | Mammary Neoplasms, Experimental | Mice | Mice, Inbred C57BL | Mice, Knockout | Reverse Transcriptase Polymerase Chain Reaction | Thymocytes | Transcription Factors | Tumor Suppressor Protein p53 | Tumor Suppressor Proteins

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Associated grants

  • Agency: Intramural NIH HHS, Id: Z01 ES101586-06
  • Agency: NIEHS NIH HHS, Id: Z01-ES-101586
  • Agency: NIEHS NIH HHS, Id: Z01-ES065079

Mouse Genome Informatics (Data, Gene Annotation)

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