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RAP80 is critical in maintaining genomic stability and suppressing tumor development
Zhengyu Yin1, Daniel Menendez, Michael A Resnick
1Laboratory of Respiratory Biology, National Institute of Environmental Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Cancer Research
|August 17, 2012
Summary
The loss of RAP80 protein impairs DNA damage response, leading to genomic instability and increased cancer susceptibility in mice. This suggests RAP80 functions as a tumor suppressor.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- RAP80 (ubiquitin interaction motif-containing protein) is crucial for DNA damage response (DDR) signaling.
- RAP80 facilitates the movement of DDR mediators like BRCA1 to DNA damage sites.
Purpose of the Study:
- To investigate the role of RAP80 in maintaining genomic stability.
- To determine the impact of RAP80 deficiency on cancer development and susceptibility.
Main Methods:
- Utilized RAP80 null (RAP80(-/-)) mice and derived mouse embryonic fibroblasts (MEFs).
- Assessed sensitivity to ionizing radiation (IR) and spontaneous/induced genomic instability.
- Evaluated tumor development in RAP80(-/-) mice, including spontaneous lymphoma and chemically induced mammary tumors.
- Examined the effect of RAP80 loss on tumor formation in p53-deficient backgrounds.
Main Results:
- RAP80(-/-) MEFs showed premature senescence and increased sensitivity to IR.
- RAP80(-/-) mice exhibited heightened spontaneous and IR-induced genomic instability.
- RAP80(-/-) thymocytes were more sensitive to IR-induced cell death.
- RAP80(-/-) mice displayed increased susceptibility to spontaneous lymphoma and mammary tumors, with accelerated tumor formation in p53-deficient mice.
Conclusions:
- RAP80 deficiency compromises genomic stability.
- Loss of RAP80 significantly increases cancer risk, supporting its role as a tumor suppressor.
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