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<table><tr><td colspan='2'>[[6h3c]] is a 10 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H3C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H3C FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6h3c]] is a 10 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H3C OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6H3C FirstGlance]. <br>
6h3c is a 10 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
[BRCC3_HUMAN] Moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome. A chromosomal aberration involving BRCC3 is a cause of pro-lymphocytic T-cell leukemia (T-PLL). Translocation t(X;14)(q28;q11) with TCRA.[1]
Function
[BABA1_HUMAN] Component of the BRCA1-A complex, a complex that specifically recognizes '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. In the BRCA1-A complex, it is required for the complex integrity and its localization at DSBs. Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:24075985, PubMed:26195665). In these 2 complexes, it is probably required to maintain the stability of BABAM2 and help the 'Lys-63'-linked deubiquitinase activity mediated by BRCC3/BRCC36 component. The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985).[2][3][4] [ABRX2_HUMAN] Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked polyubiquitin, leaving the last ubiquitin chain attached to its substrates (PubMed:19214193, PubMed:20032457, PubMed:20656690, PubMed:24075985). May act as a central scaffold protein that assembles the various components of the BRISC complex and retains them in the cytoplasm (PubMed:20656690). Plays a role in regulating the onset of apoptosis via its role in modulating 'Lys-63'-linked ubiquitination of target proteins (By similarity). Required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activities by enhancing its stability and cell surface expression (PubMed:24075985, PubMed:26344097). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). Required for normal induction of p53/TP53 in response to DNA damage (PubMed:25283148). Independent of the BRISC complex, promotes interaction between USP7 and p53/TP53, and thereby promotes deubiquitination of p53/TP53, preventing its degradation and resulting in increased p53/TP53-mediated transcription regulation and p53/TP53-dependent apoptosis in response to DNA damage (PubMed:25283148).[UniProtKB:Q3TCJ1][5][6][7][8][9] [BABA2_HUMAN] Component of the BRCA1-A complex, a complex that specifically recognizes '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 (PubMed:17525341, PubMed:19261746, PubMed:19261749, PubMed:19261748). In the BRCA1-A complex, it acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity and modulating the E3 ubiquitin ligase activity of the BRCA1-BARD1 heterodimer (PubMed:21282113, PubMed:19261748). Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:19214193, PubMed:24075985, PubMed:25283148, PubMed:26195665). Within the BRISC complex, acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity (PubMed:21282113). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). The BRISC complex plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). May play a role in homeostasis or cellular differentiation in cells of neural, epithelial and germline origins. May also act as a death receptor-associated anti-apoptotic protein, which inhibits the mitochondrial apoptotic pathway. May regulate TNF-alpha signaling through its interactions with TNFRSF1A; however these effects may be indirect (PubMed:15465831).[10][11][12][13][14][15] [BRCC3_HUMAN] Metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains (PubMed:19214193, PubMed:20656690, PubMed:24075985, PubMed:26344097). Does not have activity toward 'Lys-48'-linked polyubiquitin chains. Component of the BRCA1-A complex, a complex that specifically recognizes '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). In the BRCA1-A complex, it specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX, antagonizing the RNF8-dependent ubiquitination at double-strand breaks (DSBs) (PubMed:20656690). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:20656690, PubMed:24075985, PubMed:26344097, PubMed:26195665). Mediates the specific 'Lys-63'-specific deubiquitination associated with the COP9 signalosome complex (CSN), via the interaction of the BRISC complex with the CSN complex (PubMed:19214193). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985, PubMed:26344097). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985).[16][17][18][19][20][21][22][23][24][25][26][27] [GLYM_HUMAN] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Required to prevent uracil accumulation in mtDNA. Interconversion of serine and glycine. Associates with mitochondrial DNA.[28]
Publication Abstract from PubMed
In mammals, approximately 100 deubiquitinases act on approximately 20,000 intracellular ubiquitination sites. Deubiquitinases are commonly regarded as constitutively active, with limited regulatory and targeting capacity. The BRCA1-A and BRISC complexes serve in DNA double-strand break repair and immune signaling and contain the lysine-63 linkage-specific BRCC36 subunit that is functionalized by scaffold subunits ABRAXAS and ABRO1, respectively. The molecular basis underlying BRCA1-A and BRISC function is currently unknown. Here we show that in the BRCA1-A complex structure, ABRAXAS integrates the DNA repair protein RAP80 and provides a high-affinity binding site that sequesters the tumor suppressor BRCA1 away from the break site. In the BRISC structure, ABRO1 binds SHMT2alpha, a metabolic enzyme enabling cancer growth in hypoxic environments, which we find prevents BRCC36 from binding and cleaving ubiquitin chains. Our work explains modularity in the BRCC36 DUB family, with different adaptor subunits conferring diversified targeting and regulatory functions.
Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation.,Rabl J, Bunker RD, Schenk AD, Cavadini S, Gill ME, Abdulrahman W, Andres-Pons A, Luijsterburg MS, Ibrahim AFM, Branigan E, Aguirre JD, Marceau AH, Guerillon C, Bouwmeester T, Hassiepen U, Peters AHFM, Renatus M, Gelman L, Rubin SM, Mailand N, van Attikum H, Hay RT, Thoma NH Mol Cell. 2019 Jun 19. pii: S1097-2765(19)30435-6. doi:, 10.1016/j.molcel.2019.06.002. PMID:31253574[29]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Fisch P, Forster A, Sherrington PD, Dyer MJ, Rabbitts TH. The chromosomal translocation t(X;14)(q28;q11) in T-cell pro-lymphocytic leukaemia breaks within one gene and activates another. Oncogene. 1993 Dec;8(12):3271-6. PMID:8247530
↑ Shao G, Patterson-Fortin J, Messick TE, Feng D, Shanbhag N, Wang Y, Greenberg RA. MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes Dev. 2009 Mar 15;23(6):740-54. doi: 10.1101/gad.1739609. Epub 2009 Mar 4. PMID:19261746 doi:http://dx.doi.org/10.1101/gad.1739609
↑ 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
↑ Wang B, Hurov K, Hofmann K, Elledge SJ. NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control. Genes Dev. 2009 Mar 15;23(6):729-39. Epub 2009 Mar 4. PMID:19261749 doi:http://dx.doi.org/gad.1770309
↑ Cooper EM, Cutcliffe C, Kristiansen TZ, Pandey A, Pickart CM, Cohen RE. K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. EMBO J. 2009 Mar 18;28(6):621-31. doi: 10.1038/emboj.2009.27. Epub 2009 Feb 12. PMID:19214193 doi:http://dx.doi.org/10.1038/emboj.2009.27
↑ Cooper EM, Boeke JD, Cohen RE. Specificity of the BRISC deubiquitinating enzyme is not due to selective binding to Lys63-linked polyubiquitin. J Biol Chem. 2010 Apr 2;285(14):10344-52. doi: 10.1074/jbc.M109.059667. Epub 2009, Dec 23. PMID:20032457 doi:http://dx.doi.org/10.1074/jbc.M109.059667
↑ Feng L, Wang J, Chen J. The Lys63-specific deubiquitinating enzyme BRCC36 is regulated by two scaffold proteins localizing in different subcellular compartments. J Biol Chem. 2010 Oct 1;285(40):30982-8. doi: 10.1074/jbc.M110.135392. Epub 2010 , Jul 22. PMID:20656690 doi:http://dx.doi.org/10.1074/jbc.M110.135392
↑ Zhang J, Cao M, Dong J, Li C, Xu W, Zhan Y, Wang X, Yu M, Ge C, Ge Z, Yang X. ABRO1 suppresses tumourigenesis and regulates the DNA damage response by stabilizing p53. Nat Commun. 2014 Oct 6;5:5059. doi: 10.1038/ncomms6059. PMID:25283148 doi:http://dx.doi.org/10.1038/ncomms6059
↑ Dong Y, Hakimi MA, Chen X, Kumaraswamy E, Cooch NS, Godwin AK, Shiekhattar R. Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell. 2003 Nov;12(5):1087-99. PMID:14636569
↑ 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
↑ Wang B, Hurov K, Hofmann K, Elledge SJ. NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control. Genes Dev. 2009 Mar 15;23(6):729-39. Epub 2009 Mar 4. PMID:19261749 doi:http://dx.doi.org/gad.1770309
↑ Yan K, Li L, Wang X, Hong R, Zhang Y, Yang H, Lin M, Zhang S, He Q, Zheng D, Tang J, Yin Y, Shao G. The deubiquitinating enzyme complex BRISC is required for proper mitotic spindle assembly in mammalian cells. J Cell Biol. 2015 Jul 20;210(2):209-24. doi: 10.1083/jcb.201503039. PMID:26195665 doi:http://dx.doi.org/10.1083/jcb.201503039
↑ Li Q, Ching AK, Chan BC, Chow SK, Lim PL, Ho TC, Ip WK, Wong CK, Lam CW, Lee KK, Chan JY, Chui YL. A death receptor-associated anti-apoptotic protein, BRE, inhibits mitochondrial apoptotic pathway. J Biol Chem. 2004 Dec 10;279(50):52106-16. Epub 2004 Oct 1. PMID:15465831 doi:http://dx.doi.org/M408678200
↑ Dong Y, Hakimi MA, Chen X, Kumaraswamy E, Cooch NS, Godwin AK, Shiekhattar R. Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell. 2003 Nov;12(5):1087-99. PMID:14636569
↑ Chen X, Arciero CA, Wang C, Broccoli D, Godwin AK. BRCC36 is essential for ionizing radiation-induced BRCA1 phosphorylation and nuclear foci formation. Cancer Res. 2006 May 15;66(10):5039-46. doi: 10.1158/0008-5472.CAN-05-4194. PMID:16707425 doi:http://dx.doi.org/10.1158/0008-5472.CAN-05-4194
↑ 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
↑ 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
↑ Cooper EM, Cutcliffe C, Kristiansen TZ, Pandey A, Pickart CM, Cohen RE. K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. EMBO J. 2009 Mar 18;28(6):621-31. doi: 10.1038/emboj.2009.27. Epub 2009 Feb 12. PMID:19214193 doi:http://dx.doi.org/10.1038/emboj.2009.27
↑ Shao G, Patterson-Fortin J, Messick TE, Feng D, Shanbhag N, Wang Y, Greenberg RA. MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes Dev. 2009 Mar 15;23(6):740-54. doi: 10.1101/gad.1739609. Epub 2009 Mar 4. PMID:19261746 doi:http://dx.doi.org/10.1101/gad.1739609
↑ 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
↑ Wang B, Hurov K, Hofmann K, Elledge SJ. NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control. Genes Dev. 2009 Mar 15;23(6):729-39. Epub 2009 Mar 4. PMID:19261749 doi:http://dx.doi.org/gad.1770309
↑ Feng L, Wang J, Chen J. The Lys63-specific deubiquitinating enzyme BRCC36 is regulated by two scaffold proteins localizing in different subcellular compartments. J Biol Chem. 2010 Oct 1;285(40):30982-8. doi: 10.1074/jbc.M110.135392. Epub 2010 , Jul 22. PMID:20656690 doi:http://dx.doi.org/10.1074/jbc.M110.135392
↑ Yan K, Li L, Wang X, Hong R, Zhang Y, Yang H, Lin M, Zhang S, He Q, Zheng D, Tang J, Yin Y, Shao G. The deubiquitinating enzyme complex BRISC is required for proper mitotic spindle assembly in mammalian cells. J Cell Biol. 2015 Jul 20;210(2):209-24. doi: 10.1083/jcb.201503039. PMID:26195665 doi:http://dx.doi.org/10.1083/jcb.201503039
↑ Zeqiraj E, Tian L, Piggott CA, Pillon MC, Duffy NM, Ceccarelli DF, Keszei AF, Lorenzen K, Kurinov I, Orlicky S, Gish GD, Heck AJ, Guarne A, Greenberg RA, Sicheri F. Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function. Mol Cell. 2015 Sep 17;59(6):970-83. doi: 10.1016/j.molcel.2015.07.028. Epub 2015 , Sep 3. PMID:26344097 doi:http://dx.doi.org/10.1016/j.molcel.2015.07.028
↑ Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15163-8. doi:, 10.1073/pnas.1103623108. Epub 2011 Aug 26. PMID:21876188 doi:10.1073/pnas.1103623108
↑ Rabl J, Bunker RD, Schenk AD, Cavadini S, Gill ME, Abdulrahman W, Andres-Pons A, Luijsterburg MS, Ibrahim AFM, Branigan E, Aguirre JD, Marceau AH, Guerillon C, Bouwmeester T, Hassiepen U, Peters AHFM, Renatus M, Gelman L, Rubin SM, Mailand N, van Attikum H, Hay RT, Thoma NH. Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation. Mol Cell. 2019 Jun 19. pii: S1097-2765(19)30435-6. doi:, 10.1016/j.molcel.2019.06.002. PMID:31253574 doi:http://dx.doi.org/10.1016/j.molcel.2019.06.002
