RAP80 is critical in maintaining genomic stability and suppressing tumor development.
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.
Laboratory of Respiratory Biology, National Institute of Environmental Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Zhengyu
Z
Yin
Daniel
D
Menendez
Michael A
MA
Resnick
John E
JE
French
Kyathanahalli S
KS
Janardhan
Anton M
AM
Jetten
D000818:Animals; D001551:Benz(a)Anthracenes; D018797:Cell Cycle Proteins / Q000235:genetics*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000528:radiation effects; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability / Q000235:genetics* / Q000528:radiation effects; D056488:Histone Chaperones; D053208:Kaplan-Meier Estimate; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060168:Thymocytes / Q000378:metabolism / Q000528:radiation effects; D014157:Transcription Factors / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D001551:Benz(a)Anthracenes; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C543502:Rap80 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C046810:7,12-dihydroxymethylbenz(a)anthracene