Alternative titles; symbols
HGNC Approved Gene Symbol: UIMC1
Cytogenetic location: 5q35.2 Genomic coordinates (GRCh38) : 5:176,905,005-177,022,602 (from NCBI)
By differential display of RNA expressed by young proliferating and senescent normal human epidermal keratinocytes, followed by screening a testis cDNA library, Yan et al. (2002) cloned RAP80. The deduced 719-amino acid protein has a calculated molecular mass of 79.6 kD. The N-terminal half of RAP80 contains 2 nuclear localization signals and a putative ubiquitin interaction motif. The C-terminal half contains a potential PEST sequence, 2 zinc fingers, and a third nuclear localization signal. Northern blot analysis detected a major 2.6-kb transcript expressed highly in testis and moderately in ovary, thymus, and heart. In situ hybridization of mouse testis detected Rap80 associated with germ cells, with little expression in surrounding Leydig cells. No significant differences in the level of Rap80 were found between developmental subpopulations of germ cells, suggesting that Rap80 expression is not developmentally regulated. Immunofluorescence localization detected RAP80 in a speckled nuclear distribution in a transfected monkey kidney cell line, and mutation analysis indicated that the second nuclear localization signal directed intracellular localization.
Yan et al. (2002) found that RAP80 decreased basal transcription of a reporter gene in transfected Chinese hamster ovary and monkey kidney cell lines. Yeast 2-hybrid analysis indicated that RAP80 could interact with the retinoid-related testis-associated receptor (RTR; 602778), but not with retinoid receptors (see RXRA; 180245) or other nuclear receptors tested. Cotransfection experiments showed that RAP80 and RTR interacted with each other in a dose-dependent manner. Mutation analysis indicated that several regions of RAP80 were important for optimal interaction with RTR. RAP80 inhibited the interaction of NCOR (600849) with RTR in a concentration-dependent manner, and RAP80 and NCOR appeared to compete with each other for RTR binding.
Wang et al. (2007) showed that Abraxas (ABRA1; 611143), a protein that binds BRCA1 (113705), recruits the ubiquitin-interacting motif (UIM)-containing protein RAP80 to the BRCA1 complex. Both Abraxas and RAP80 were required for DNA damage resistance, G2/M checkpoint control, and DNA repair. RAP80 was required for optimal accumulation of BRCA1 on damaged DNA (foci) in response to ionizing radiation, and the UIM domains alone were capable of foci formation. Wang et al. (2007) concluded that the RAP80-Abraxas complex may help recruit BRCA1 to DNA damage sites in part through recognition of ubiquitinated proteins.
Sobhian et al. (2007) reported the interaction of the BRCT (BRCA1 C-terminal) BRCA1 domain with the ubiquitin-binding protein RAP80. RAP80 targets a complex containing the BRCA1-BARD1 (601593) E3 ligase and the deubiquitinating enzyme BRCC36 (300617) to MDC1 (607593)-gamma-H2AX (601772)-dependent lys6- and lys63-linked ubiquitin polymers at double-strand breaks. Sobhian et al. (2007) stated that these events are required for cell cycle checkpoint and repair responses to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of double-strand breaks.
Kim et al. (2007) independently reported the identification of AP80 as a BRCA1-interacting protein in humans. RAP80 contains a tandem UIM domain, which is required for its binding with ubiquitin in vitro and its damage-induced foci formation in vivo. Moreover, Kim et al. (2007) showed that RAP80 specifically recruits BRCA1 to DNA damage sites and functions with BRCA1 in G2/M checkpoint control. Kim et al. (2007) concluded that taken together, their results suggested the existence of a ubiquitination-dependent signaling pathway involved in the DNA damage response.
Yan et al. (2002) determined that the RAP80 gene contains 15 exons and spans more than 90 kb.
By FISH, Yan et al. (2002) mapped the RAP80 gene to chromosome 5q35.
Kim, H., Chen, J., Yu, X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316: 1202-1205, 2007. [PubMed: 17525342] [Full Text: https://doi.org/10.1126/science.1139621]
Sobhian, B., Shao, G., Lilli, D. R., Culhane, A. C., Moreau, L. A., Xia, B., Livingston, D. M., Greenberg, R. A. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316: 1198-1202, 2007. [PubMed: 17525341] [Full Text: https://doi.org/10.1126/science.1139516]
Wang, B., Matsuoka, S., Ballif, B. A., Zhang, D., Smogorzewska, A., Gygi, S. P., Elledge, S. J. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316: 1194-1198, 2007. [PubMed: 17525340] [Full Text: https://doi.org/10.1126/science.1139476]
Yan, Z., Kim, Y.-S., Jetten, A. M. RAP80, a novel nuclear protein that interacts with the retinoid-related testis-associated receptor. J. Biol. Chem. 277: 32379-32388, 2002. [PubMed: 12080054] [Full Text: https://doi.org/10.1074/jbc.M203475200]