| 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] [SUMO2_HUMAN] Ubiquitin-like protein that can be covalently attached to proteins as a monomer or as a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by an E3 ligase such as PIAS1-4, RANBP2 or CBX4. This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Polymeric SUMO2 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins.[10] [11] [12]
Publication Abstract from PubMed
Recognition and repair of double stranded DNA breaks (DSB) involves the targeted recruitment of BRCA tumor suppressors to damage foci through binding of both ubiquitin (Ub) and the Ub-like modifier SUMO. RAP80 is a component of the BRCA1 A complex, and plays a key role in the recruitment process through the binding of K63-linked polyUb chains by tandem Ub interacting motifs (UIM). RAP80 also contains a SUMO interacting motif (SIM) just upstream of the tandem UIMs that has been shown to specifically bind the SUMO-2 isoform. The RAP80 tandem UIMs and SIM function collectively for optimal recruitment of BRCA1 to DSBs, though the molecular basis of this process is not well understood. Using NMR spectroscopy, we demonstrate that the RAP80 SIM binds SUMO-2, and that both specificity and affinity are enhanced through phosphorylation of the canonical CK2 site within the SIM. The affinity increase results from an enhancement of electrostatic interactions between the phosphoserines of RAP80 and the SIM recognition module within SUMO-2. The NMR structure of the SUMO-2/phosphoRAP80 complex reveals that the molecular basis for SUMO-2 specificity is due to isoform-specific sequence differences in electrostatic SIM recognition modules.
Molecular Basis for Phosphorylation Dependent SUMO Recognition by the DNA Repair Protein RAP80.,Anamika, Spyracopoulos L J Biol Chem. 2015 Dec 30. pii: jbc.M115.705061. PMID:26719330[13]
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
- ↑ Kamitani T, Kito K, Nguyen HP, Fukuda-Kamitani T, Yeh ET. Characterization of a second member of the sentrin family of ubiquitin-like proteins. J Biol Chem. 1998 May 1;273(18):11349-53. PMID:9556629
- ↑ Meulmeester E, Kunze M, Hsiao HH, Urlaub H, Melchior F. Mechanism and consequences for paralog-specific sumoylation of ubiquitin-specific protease 25. Mol Cell. 2008 Jun 6;30(5):610-9. doi: 10.1016/j.molcel.2008.03.021. PMID:18538659 doi:10.1016/j.molcel.2008.03.021
- ↑ Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, Palvimo JJ, Hay RT. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol. 2008 May;10(5):538-46. doi: 10.1038/ncb1716. Epub 2008 Apr 13. PMID:18408734 doi:10.1038/ncb1716
- ↑ Anamika, Spyracopoulos L. Molecular Basis for Phosphorylation Dependent SUMO Recognition by the DNA Repair Protein RAP80. J Biol Chem. 2015 Dec 30. pii: jbc.M115.705061. PMID:26719330 doi:http://dx.doi.org/10.1074/jbc.M115.705061
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