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Cancer Res. 2012 Oct 1;72(19):5080-90. doi: 10.1158/0008-5472.CAN-12-1484. Epub 2012 Aug 15.

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

Author information

1
Laboratory of Respiratory Biology, National Institute of Environmental Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.

Abstract

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.

PMID:
22896338
PMCID:
PMC3482830
DOI:
10.1158/0008-5472.CAN-12-1484
[Indexed for MEDLINE]
Free PMC Article

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