| Structural highlights
Function
[UIMC1_HUMAN] Ubiquitin-binding protein that specifically recognizes and binds 'Lys-63'-linked ubiquitin. Plays a central role in the BRCA1-A complex by specifically binding 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX. Also weakly binds monoubiquitin but with much less affinity than 'Lys-63'-linked ubiquitin. May interact with monoubiquitinated histones H2A and H2B; the relevance of such results is however unclear in vivo. Does not bind Lys-48'-linked ubiquitin. May indirectly act as a transcriptional repressor by inhibiting the interaction of NR6A1 with the corepressor NCOR1.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
Signal transduction within the DNA damage response is driven by the flux of protein-protein interaction cascades that ultimately recruit repair complexes to sites of damage. The protein RAP80 plays a central role in the damage response by targeting BRCA1/BRCA2 tumor suppressors to DNA damage foci through multivalent binding of K63-linked polyubiquitin chains. Mutations within the high penetrance BRCA1/BRCA2 genes account for ~20% of familial breast cancers. The genetic basis for the remaining cancers remains unknown, but may involve defects in binding partners for BRCA1 and BRCA2 that lead to impaired targeting to foci and a concomittant role in the pathogenesis of cancer. Recently, an in-frame deletion mutation (DeltaE81) in a conserved region from the first ubiquitin interaction motif (UIM) of RAP80 has been linked to an increase in chromosomal abnormalities. Using NMR spectroscopy, we demonstrate that the N-cap motif within the Delta-helix of the first UIM from DeltaE81 undergoes a structural frameshift that leads to abolishment of multivalent binding of polyubiquitin chains. Loss of this single glutamate residue disrupts favorable electrostatic interactions between RAP80 and ubiquitin, establishing a plausible molecular basis for a potential predisposition to cancer unrelated to mutations within BRCA1/BRCA2 genes.
Molecular Basis for Impaired DNA Damage Response Function Associated with the RAP80 DeltaE81 Defect.,Anamika A, Markin CJ, Rout MK, Spyracopoulos L J Biol Chem. 2014 Mar 13. PMID:24627472[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yan Z, Kim YS, Jetten AM. RAP80, a novel nuclear protein that interacts with the retinoid-related testis-associated receptor. J Biol Chem. 2002 Aug 30;277(35):32379-88. Epub 2002 Jun 21. PMID:12080054 doi:http://dx.doi.org/10.1074/jbc.M203475200
- ↑ Yan J, Kim YS, Yang XP, Li LP, Liao G, Xia F, Jetten AM. The ubiquitin-interacting motif containing protein RAP80 interacts with BRCA1 and functions in DNA damage repair response. Cancer Res. 2007 Jul 15;67(14):6647-56. Epub 2007 Jul 9. PMID:17621610 doi:http://dx.doi.org/0008-5472.CAN-07-0924
- ↑ Liu Z, Wu J, Yu X. CCDC98 targets BRCA1 to DNA damage sites. Nat Struct Mol Biol. 2007 Aug;14(8):716-20. Epub 2007 Jul 22. PMID:17643121 doi:http://dx.doi.org/nsmb1279
- ↑ Wang B, Matsuoka S, Ballif BA, Zhang D, Smogorzewska A, Gygi SP, Elledge SJ. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science. 2007 May 25;316(5828):1194-8. PMID:17525340 doi:10.1126/science.1139476
- ↑ Sobhian B, Shao G, Lilli DR, Culhane AC, Moreau LA, Xia B, Livingston DM, Greenberg RA. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science. 2007 May 25;316(5828):1198-202. PMID:17525341 doi:http://dx.doi.org/316/5828/1198
- ↑ Kim H, Chen J, Yu X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science. 2007 May 25;316(5828):1202-5. PMID:17525342 doi:http://dx.doi.org/10.1126/science.1139621
- ↑ Feng L, Huang J, Chen J. MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes Dev. 2009 Mar 15;23(6):719-28. doi: 10.1101/gad.1770609. Epub 2009 Mar 4. PMID:19261748 doi:10.1101/gad.1770609
- ↑ Wu J, Huen MS, Lu LY, Ye L, Dou Y, Ljungman M, Chen J, Yu X. Histone ubiquitination associates with BRCA1-dependent DNA damage response. Mol Cell Biol. 2009 Feb;29(3):849-60. doi: 10.1128/MCB.01302-08. Epub 2008 Nov, 17. PMID:19015238 doi:http://dx.doi.org/10.1128/MCB.01302-08
- ↑ Shao G, Lilli DR, Patterson-Fortin J, Coleman KA, Morrissey DE, Greenberg RA. The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3166-71. doi:, 10.1073/pnas.0807485106. Epub 2009 Feb 6. PMID:19202061 doi:http://dx.doi.org/10.1073/pnas.0807485106
- ↑ Anamika A, Markin CJ, Rout MK, Spyracopoulos L. Molecular Basis for Impaired DNA Damage Response Function Associated with the RAP80 DeltaE81 Defect. J Biol Chem. 2014 Mar 13. PMID:24627472 doi:http://dx.doi.org/10.1074/jbc.M113.538280
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