BARD1

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BRCA1 associated RING domain 1
Protein BARD1 PDB 1jm7.png
PDB rendering based on 1jm7.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbol BARD1
External IDs OMIM601593 MGI1328361 HomoloGene400 ChEMBL: 1741211 GeneCards: BARD1 Gene
RNA expression pattern
PBB GE BARD1 205345 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 580 12021
Ensembl ENSG00000138376 ENSMUSG00000026196
UniProt Q99728 O70445
RefSeq (mRNA) NM_000465 NM_007525
RefSeq (protein) NP_000456 NP_031551
Location (UCSC) Chr 2:
214.73 – 214.81 Mb
Chr 1:
71.03 – 71.1 Mb
PubMed search [1] [2]

BRCA1-associated RING domain protein 1 is a protein that in humans is encoded by the BARD1 gene.[1][2][3] The human BARD1 protein is 777 amino acids long and contains a RING finger domain (residues 46-90), three ankyrin repeats (residues 420-5250), and two tandem BRCT domains (residues 568-777).[4]

Function[edit]

Most, if not all, BRCA1 heterodimerizes with BARD1 in vivo.[5] BARD1 and BRCA1 form a heterodimer via their N-terminal RING finger domains. The BARD1-BRCA1 interaction is observed in vivo and in vitro and is essential for BRCA1 stability. BARD1 shares homology with the two most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes, and developmentally important genes such as the polycomb group of genes. The BARD1 protein also contains three tandem ankyrin repeats. [6]

The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. BARD1 may be the target of oncogenic mutations in breast or ovarian cancer.[6] Mutations in the BARD1 protein that affect its structure appear in many breast, ovarian, and uterine cancers, suggesting the mutations disable BARD1's tumor suppressor function.[7] Three missense mutations, each affecting BARD1's BRCT domain, are known to be implicated in cancers: C645R is associated with breast and ovarian cancers, V695L is associated with breast cancer, and S761N is associated with breast and uterine cancers.[8] BARD1 expression is upregulated by genotoxic stress and involved in apoptosis through binding and stabilizing p53 independently of BRCA1.[9]

BARD1 is vital in the rapid relocation of BRCA1 to DNA damage sites.[10] BARD1 tandem BRCA1 C-terminus (BRCT) motifs fold into a binding pocket with a key lysine residue (K619), and bind to poly(ADP-ribose) (PAR), which targets the BRCA1/BARD1 heterodimer to damaged DNA sites.[10] Double stranded breaks (DSB) in DNA trigger poly(ADPribose) polymerase 1 (PARP1) to catalyze the formation of poly(ADPribose) (PAR) so that PAR can then bind to an array of DNA response proteins, including the BRCA1/BARD1 heterodimer, and target them to DNA damage sites.[11] When the BRCA1/BARD1 heterodimer is transported to the damaged DNA site, it acts as an E3 ubiquitin ligase.[12] The BRCA1/BARD1 heterodimer ubiquitinates RNA polymerase II, preventing the transcription of the damaged DNA, and restoring genetic stability. [13]

Interactions[edit]

BARD1 has been shown to interact with:

Implication in Cancer Treatments[edit]

If a cancer cell's capacity to repair DNA damage were incapacitated, cancer treatments would be more effective. Inhibiting cancer cells' BRCA1/BARD1 heterodimer from relocating to DNA damage sites would target these cells for apoptosis rather than repair. One inhibition possibility is the BARD1 BRCT key lysine residue (K619). Inhibiting this lysine residue's ability to bind poly(ADP-ribose) would prevent the BRCA1/BARD1 heterodimer from localizing to DNA damage sites and subsequently prevent DNA damage repair. This would make cancer therapies such as chemotherapy and radiation vastly more effective. [46]

References[edit]

  1. ^ a b Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A, Xu XL et al. (Dec 1996). "Identification of a RING protein that can interact in vivo with the BRCA1 gene product". Nature Genetics 14 (4): 430–40. doi:10.1038/ng1296-430. PMID 8944023. 
  2. ^ Thai TH, Du F, Tsan JT, Jin Y, Phung A, Spillman MA et al. (Feb 1998). "Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers". Human Molecular Genetics 7 (2): 195–202. doi:10.1093/hmg/7.2.195. PMID 9425226. 
  3. ^ a b Fabbro M, Savage K, Hobson K, Deans AJ, Powell SN, McArthur GA et al. (Jul 2004). "BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage". The Journal of Biological Chemistry 279 (30): 31251–8. doi:10.1074/jbc.M405372200. PMID 15159397. 
  4. ^ Birrane, G.; Varma, A.K.; Soni, A.; Ladias, J.A. (2007). "Crystal Structure of the BARD1 BRCT domains". Biochemistry 46 (26): 7706–7712. 
  5. ^ Baer R, Ludwig T (Feb 2002). "The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity". Current Opinion in Genetics & Development 12 (1): 86–91. PMID 11790560. 
  6. ^ a b "Entrez Gene: BARD1 BRCA1 associated RING domain 1". 
  7. ^ Birrane G, Varma AK, Soni A, Ladias JA (Jul 2007). "Crystal structure of the BARD1 BRCT domains". Biochemistry 46 (26): 7706–12. doi:10.1021/bi700323t. PMID 17550235. 
  8. ^ Birrane G, Varma AK, Soni A, Ladias JA (Jul 2007). "Crystal structure of the BARD1 BRCT domains". Biochemistry 46 (26): 7706–12. doi:10.1021/bi700323t. PMID 17550235. 
  9. ^ Irminger-Finger I, Leung WC, Li J, Dubois-Dauphin M, Harb J, Feki A et al. (Dec 2001). "Identification of BARD1 as mediator between proapoptotic stress and p53-dependent apoptosis". Molecular Cell 8 (6): 1255–66. doi:10.1016/s1097-2765(01)00406-3. PMID 11779501. 
  10. ^ a b Li M, Yu X (May 2013). "Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation". Cancer Cell 23 (5): 693–704. doi:10.1016/j.ccr.2013.03.025. PMID 23680151. 
  11. ^ Baer R (May 2013). "Luring BRCA1 to the scene of the crime". Cancer Cell 23 (5): 565–7. doi:10.1016/j.ccr.2013.04.013. PMID 23680142. 
  12. ^ Baer R, Ludwig T (Feb 2002). "The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity". Current Opinion in Genetics & Development 12 (1): 86–91. PMID 11790560. 
  13. ^ Irminger-Finger I, Jefford CE (May 2006). "Is there more to BARD1 than BRCA1?". Nature Reviews. Cancer 6 (5): 382–91. doi:10.1038/nrc1878. PMID 16633366. 
  14. ^ a b c d Ryser S, Dizin E, Jefford CE, Delaval B, Gagos S, Christodoulidou A et al. (Feb 2009). "Distinct roles of BARD1 isoforms in mitosis: full-length BARD1 mediates Aurora B degradation, cancer-associated BARD1beta scaffolds Aurora B and BRCA2". Cancer Research 69 (3): 1125–34. doi:10.1158/0008-5472.CAN-08-2134. PMID 19176389. 
  15. ^ Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG et al. (Jun 1999). "The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators". Oncogene 18 (22): 3316–23. doi:10.1038/sj.onc.1202717. PMID 10362352. 
  16. ^ a b c d e f g Dong Y, Hakimi MA, Chen X, Kumaraswamy E, Cooch NS, Godwin AK et al. (Nov 2003). "Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair". Molecular Cell 12 (5): 1087–99. doi:10.1016/S1097-2765(03)00424-6. PMID 14636569. 
  17. ^ a b c Mallery DL, Vandenberg CJ, Hiom K (Dec 2002). "Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains". The EMBO Journal 21 (24): 6755–62. doi:10.1093/emboj/cdf691. PMC 139111. PMID 12485996. 
  18. ^ a b Kentsis A, Gordon RE, Borden KL (Nov 2002). "Control of biochemical reactions through supramolecular RING domain self-assembly". Proceedings of the National Academy of Sciences of the United States of America 99 (24): 15404–9. doi:10.1073/pnas.202608799. PMC 137729. PMID 12438698. 
  19. ^ a b c Chen A, Kleiman FE, Manley JL, Ouchi T, Pan ZQ (Jun 2002). "Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase". The Journal of Biological Chemistry 277 (24): 22085–92. doi:10.1074/jbc.M201252200. PMID 11927591. 
  20. ^ a b c Sato K, Hayami R, Wu W, Nishikawa T, Nishikawa H, Okuda Y et al. (Jul 2004). "Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase". The Journal of Biological Chemistry 279 (30): 30919–22. doi:10.1074/jbc.C400169200. PMID 15184379. 
  21. ^ a b Wu-Baer F, Lagrazon K, Yuan W, Baer R (Sep 2003). "The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin". The Journal of Biological Chemistry 278 (37): 34743–6. doi:10.1074/jbc.C300249200. PMID 12890688. 
  22. ^ a b c Vandenberg CJ, Gergely F, Ong CY, Pace P, Mallery DL, Hiom K et al. (Jul 2003). "BRCA1-independent ubiquitination of FANCD2". Molecular Cell 12 (1): 247–54. doi:10.1016/S1097-2765(03)00281-8. PMID 12887909. 
  23. ^ a b Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D, Yabuki Y et al. (May 2001). "The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation". The Journal of Biological Chemistry 276 (18): 14537–40. doi:10.1074/jbc.C000881200. PMID 11278247. 
  24. ^ a b c Kleiman FE, Manley JL (Mar 2001). "The BARD1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression". Cell 104 (5): 743–53. doi:10.1016/S0092-8674(01)00270-7. PMID 11257228. 
  25. ^ a b c Kleiman FE, Manley JL (Sep 1999). "Functional interaction of BRCA1-associated BARD1 with polyadenylation factor CstF-50". Science 285 (5433): 1576–9. doi:10.1126/science.285.5433.1576. PMID 10477523. 
  26. ^ Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T et al. (Aug 2001). "Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1". Oncogene 20 (34): 4640–9. doi:10.1038/sj.onc.1204625. PMID 11498787. 
  27. ^ Fabbro M, Rodriguez JA, Baer R, Henderson BR (Jun 2002). "BARD1 induces BRCA1 intranuclear foci formation by increasing RING-dependent BRCA1 nuclear import and inhibiting BRCA1 nuclear export". The Journal of Biological Chemistry 277 (24): 21315–24. doi:10.1074/jbc.M200769200. PMID 11925436. 
  28. ^ Rodriguez JA, Schüchner S, Au WW, Fabbro M, Henderson BR (Mar 2004). "Nuclear-cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1". Oncogene 23 (10): 1809–20. doi:10.1038/sj.onc.1207302. PMID 14647430. 
  29. ^ Brzovic PS, Keeffe JR, Nishikawa H, Miyamoto K, Fox D, Fukuda M et al. (May 2003). "Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex". Proceedings of the National Academy of Sciences of the United States of America 100 (10): 5646–51. doi:10.1073/pnas.0836054100. PMC 156255. PMID 12732733. 
  30. ^ Nishikawa H, Ooka S, Sato K, Arima K, Okamoto J, Klevit RE et al. (Feb 2004). "Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase". The Journal of Biological Chemistry 279 (6): 3916–24. doi:10.1074/jbc.M308540200. PMID 14638690. 
  31. ^ Chiba N, Parvin JD (Oct 2001). "Redistribution of BRCA1 among four different protein complexes following replication blockage". The Journal of Biological Chemistry 276 (42): 38549–54. doi:10.1074/jbc.M105227200. PMID 11504724. 
  32. ^ Morris JR, Keep NH, Solomon E (Mar 2002). "Identification of residues required for the interaction of BARD1 with BRCA1". The Journal of Biological Chemistry 277 (11): 9382–6. doi:10.1074/jbc.M109249200. PMID 11773071. 
  33. ^ Brzovic PS, Meza JE, King MC, Klevit RE (Nov 2001). "BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein-protein interactions". The Journal of Biological Chemistry 276 (44): 41399–406. doi:10.1074/jbc.M106551200. PMID 11526114. 
  34. ^ Xia Y, Pao GM, Chen HW, Verma IM, Hunter T (Feb 2003). "Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein". The Journal of Biological Chemistry 278 (7): 5255–63. doi:10.1074/jbc.M204591200. PMID 12431996. 
  35. ^ Meza JE, Brzovic PS, King MC, Klevit RE (Feb 1999). "Mapping the functional domains of BRCA1. Interaction of the ring finger domains of BRCA1 and BARD1". The Journal of Biological Chemistry 274 (9): 5659–65. doi:10.1074/jbc.274.9.5659. PMID 10026184. 
  36. ^ Brzovic PS, Rajagopal P, Hoyt DW, King MC, Klevit RE (Oct 2001). "Structure of a BRCA1-BARD1 heterodimeric RING-RING complex". Nature Structural Biology 8 (10): 833–7. doi:10.1038/nsb1001-833. PMID 11573085. 
  37. ^ Yu X, Wu LC, Bowcock AM, Aronheim A, Baer R (Sep 1998). "The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression". The Journal of Biological Chemistry 273 (39): 25388–92. doi:10.1074/jbc.273.39.25388. PMID 9738006. 
  38. ^ Jin Y, Xu XL, Yang MC, Wei F, Ayi TC, Bowcock AM et al. (Oct 1997). "Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains". Proceedings of the National Academy of Sciences of the United States of America 94 (22): 12075–80. doi:10.1073/pnas.94.22.12075. PMC 23707. PMID 9342365. 
  39. ^ Scully R, Ganesan S, Vlasakova K, Chen J, Socolovsky M, Livingston DM (Dec 1999). "Genetic analysis of BRCA1 function in a defined tumor cell line". Molecular Cell 4 (6): 1093–9. doi:10.1016/S1097-2765(00)80238-5. PMID 10635334. 
  40. ^ Tascou S, Kang TW, Trappe R, Engel W, Burfeind P (Sep 2003). "Identification and characterization of NIF3L1 BP1, a novel cytoplasmic interaction partner of the NIF3L1 protein". Biochemical and Biophysical Research Communications 309 (2): 440–8. doi:10.1016/j.bbrc.2003.07.008. PMID 12951069. 
  41. ^ Benezra M, Chevallier N, Morrison DJ, MacLachlan TK, El-Deiry WS, Licht JD (Jul 2003). "BRCA1 augments transcription by the NF-kappaB transcription factor by binding to the Rel domain of the p65/RelA subunit". The Journal of Biological Chemistry 278 (29): 26333–41. doi:10.1074/jbc.M303076200. PMID 12700228. 
  42. ^ Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S et al. (Apr 2001). "BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function". Cell 105 (1): 149–60. doi:10.1016/S0092-8674(01)00304-X. PMID 11301010. 
  43. ^ Wang Q, Zhang H, Kajino K, Greene MI (Oct 1998). "BRCA1 binds c-Myc and inhibits its transcriptional and transforming activity in cells". Oncogene 17 (15): 1939–48. doi:10.1038/sj.onc.1202403. PMID 9788437. 
  44. ^ Nishikawa H, Wu W, Koike A, Kojima R, Gomi H, Fukuda M et al. (Jan 2009). "BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity". Cancer Research 69 (1): 111–9. doi:10.1158/0008-5472.CAN-08-3355. PMID 19117993. 
  45. ^ Spahn L, Petermann R, Siligan C, Schmid JA, Aryee DN, Kovar H (Aug 2002). "Interaction of the EWS NH2 terminus with BARD1 links the Ewing's sarcoma gene to a common tumor suppressor pathway". Cancer Research 62 (16): 4583–7. PMID 12183411. 
  46. ^ Venkitaraman, A.R. (2002). "Cancer Suseptibility and the Functions of BRCA1 and BRCA2". Cell 108 (2): 171–182. Retrieved 25 May 2015. 

Further reading[edit]

  • Irminger-Finger I, Leung WC (Jun 2002). "BRCA1-dependent and independent functions of BARD1". The International Journal of Biochemistry & Cell Biology 34 (6): 582–7. doi:10.1016/S1357-2725(01)00161-3. PMID 11943588. 
  • Irminger-Finger I (Jun 2003). "3rd Geneva aging workshop 2002: cancer, apoptosis and aging". Biochimica Et Biophysica Acta 1653 (1): 41–5. doi:10.1016/S0304-419X(03)00019-2. PMID 12781370. 
  • Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
  • Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548. 
  • Jin Y, Xu XL, Yang MC, Wei F, Ayi TC, Bowcock AM et al. (Oct 1997). "Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains". Proceedings of the National Academy of Sciences of the United States of America 94 (22): 12075–80. doi:10.1073/pnas.94.22.12075. PMC 23707. PMID 9342365. 
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
  • Yu X, Wu LC, Bowcock AM, Aronheim A, Baer R (Sep 1998). "The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression". The Journal of Biological Chemistry 273 (39): 25388–92. doi:10.1074/jbc.273.39.25388. PMID 9738006. 
  • Ayi TC, Tsan JT, Hwang LY, Bowcock AM, Baer R (Oct 1998). "Conservation of function and primary structure in the BRCA1-associated RING domain (BARD1) protein". Oncogene 17 (16): 2143–8. doi:10.1038/sj.onc.1202123. PMID 9798686. 
  • Meza JE, Brzovic PS, King MC, Klevit RE (Feb 1999). "Mapping the functional domains of BRCA1. Interaction of the ring finger domains of BRCA1 and BARD1". The Journal of Biological Chemistry 274 (9): 5659–65. doi:10.1074/jbc.274.9.5659. PMID 10026184. 
  • Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG et al. (Jun 1999). "The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators". Oncogene 18 (22): 3316–23. doi:10.1038/sj.onc.1202717. PMID 10362352. 
  • Kleiman FE, Manley JL (Sep 1999). "Functional interaction of BRCA1-associated BARD1 with polyadenylation factor CstF-50". Science 285 (5433): 1576–9. doi:10.1126/science.285.5433.1576. PMID 10477523. 
  • Scully R, Ganesan S, Vlasakova K, Chen J, Socolovsky M, Livingston DM (Dec 1999). "Genetic analysis of BRCA1 function in a defined tumor cell line". Molecular Cell 4 (6): 1093–9. doi:10.1016/S1097-2765(00)80238-5. PMID 10635334. 
  • Yu X, Baer R (Jun 2000). "Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor". The Journal of Biological Chemistry 275 (24): 18541–9. doi:10.1074/jbc.M909494199. PMID 10764811. 
  • Kleiman FE, Manley JL (Mar 2001). "The BARD1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression". Cell 104 (5): 743–53. doi:10.1016/S0092-8674(01)00270-7. PMID 11257228. 
  • Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D, Yabuki Y et al. (May 2001). "The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation". The Journal of Biological Chemistry 276 (18): 14537–40. doi:10.1074/jbc.C000881200. PMID 11278247. 
  • Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T et al. (Aug 2001). "Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1". Oncogene 20 (34): 4640–9. doi:10.1038/sj.onc.1204625. PMID 11498787. 
  • Chiba N, Parvin JD (Oct 2001). "Redistribution of BRCA1 among four different protein complexes following replication blockage". The Journal of Biological Chemistry 276 (42): 38549–54. doi:10.1074/jbc.M105227200. PMID 11504724. 
  • Brzovic PS, Meza JE, King MC, Klevit RE (Nov 2001). "BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein-protein interactions". The Journal of Biological Chemistry 276 (44): 41399–406. doi:10.1074/jbc.M106551200. PMID 11526114.