Biology:BARD1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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), four ankyrin repeats (residues 420-555), and a tandem BRCT domain (residues 568-777).[4][5]

Function

Most, if not all, BRCA1 heterodimerizes with BARD1 in vivo.[6] 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.[5][7][8]

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.[7] 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.[4] 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.[4] 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.[6] The BRCA1/BARD1 heterodimer ubiquitinates RNA polymerase II, preventing the transcription of the damaged DNA, and restoring genetic stability.[12]

DNA repair

BRCA1/BARD1 appears to have an important function in the recruitment of RAD51 protein to DNA double-strand breaks which is a crucial early step in the homologous recombinational repair of these breaks.[13] It is likely that BRCA1/BARD1 functions as part of a higher-order "homologous recombination mediator complex" along with two other tumor suppressor proteins BRCA2 and PALB2.[13]

Additionally, the BRCA1/BARD1 heterodimer seems to antagonistically compete with the tumor suppressor 53BP1 to promote the homologous recombination pathway rather than non-homologous end joining during double-strand break repair.[14] Specifically, methylation of the H4K20 dimethylation mark (H4K20me2), found in large amounts in parental and unreplicated chromatin, supports 53BP1 recruitment.[15] However, in nascent chromosomes, where H4K20me2 is mostly diluted, H4K20me0-mediated recruitment of BRCA1/BARD1 increases, suggesting a role in cell-cycle-dependent DNA repair.[14]

Interactions

BARD1 has been shown to interact with:

Applications

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 induce tumor cell death 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.[29]

References

  1. ↑ 1.0 1.1 "Identification of a RING protein that can interact in vivo with the BRCA1 gene product". Nature Genetics 14 (4): 430–40. Dec 1996. doi:10.1038/ng1296-430. PMID 8944023. 
  2. ↑ "Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers". Human Molecular Genetics 7 (2): 195–202. Feb 1998. doi:10.1093/hmg/7.2.195. PMID 9425226. 
  3. ↑ 3.0 3.1 "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. Jul 2004. doi:10.1074/jbc.M405372200. PMID 15159397. 
  4. ↑ 4.0 4.1 4.2 "Crystal structure of the BARD1 BRCT domains". Biochemistry 46 (26): 7706–12. Jul 2007. doi:10.1021/bi700323t. PMID 17550235. 
  5. ↑ 5.0 5.1 "Mechanisms of BRCA1-BARD1 nucleosome recognition and ubiquitylation". Nature 596 (7872): 438–43. Aug 2021. doi:10.1038/s41586-021-03716-8. PMID 34321665. Bibcode: 2021Natur.596..438H. 
  6. ↑ 6.0 6.1 "The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity". Current Opinion in Genetics & Development 12 (1): 86–91. Feb 2002. doi:10.1016/s0959-437x(01)00269-6. PMID 11790560. 
  7. ↑ 7.0 7.1 "Entrez Gene: BARD1 BRCA1 associated RING domain 1". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=580. 
  8. ↑ Fox, David; Le Trong, Isolde; Rajagopal, Ponni; Brzovic, Peter S.; Stenkamp, Ronald E.; Klevit, Rachel E. (2008-07-25). "Crystal structure of the BARD1 ankyrin repeat domain and its functional consequences". The Journal of Biological Chemistry 283 (30): 21179–21186. doi:10.1074/jbc.M802333200. ISSN 0021-9258. PMID 18480049. 
  9. ↑ "Identification of BARD1 as mediator between proapoptotic stress and p53-dependent apoptosis". Molecular Cell 8 (6): 1255–66. Dec 2001. doi:10.1016/s1097-2765(01)00406-3. PMID 11779501. 
  10. ↑ 10.0 10.1 "Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation". Cancer Cell 23 (5): 693–704. May 2013. doi:10.1016/j.ccr.2013.03.025. PMID 23680151. 
  11. ↑ "Luring BRCA1 to the scene of the crime". Cancer Cell 23 (5): 565–7. May 2013. doi:10.1016/j.ccr.2013.04.013. PMID 23680142. 
  12. ↑ "Is there more to BARD1 than BRCA1?". Nature Reviews. Cancer 6 (5): 382–91. May 2006. doi:10.1038/nrc1878. PMID 16633366. 
  13. ↑ 13.0 13.1 Tarsounas M, Sung P. The antitumorigenic roles of BRCA1-BARD1 in DNA repair and replication. Nat Rev Mol Cell Biol. 2020;21(5):284-299. doi:10.1038/s41580-020-0218-z
  14. ↑ 14.0 14.1 Michelena, Jone; Pellegrino, Stefania; Spegg, Vincent; Altmeyer, Matthias (2021). "Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and BRCA1-deficient cells" (in en). Life Science Alliance 4 (6). doi:10.26508/lsa.202101023. PMID 33811064. 
  15. ↑ Simonetta, Marco; de Krijger, Inge; Serrat, Judit; Moatti, Nathalie; Fortunato, Diogo; Hoekman, Liesbeth; Bleijerveld, Onno B.; Altelaar, A. F. Maarten et al. (2018-01-02). "H4K20me2 distinguishes pre-replicative from post-replicative chromatin to appropriately direct DNA repair pathway choice by 53BP1-RIF1-MAD2L2" (in en). Cell Cycle 17 (1): 124–136. doi:10.1080/15384101.2017.1404210. ISSN 1538-4101. PMID 29160738. 
  16. ↑ 16.0 16.1 16.2 16.3 "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. Feb 2009. doi:10.1158/0008-5472.CAN-08-2134. PMID 19176389. 
  17. ↑ "The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators". Oncogene 18 (22): 3316–23. Jun 1999. doi:10.1038/sj.onc.1202717. PMID 10362352. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 "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. Nov 2003. doi:10.1016/S1097-2765(03)00424-6. PMID 14636569. 
  19. ↑ 19.0 19.1 19.2 "Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains". The EMBO Journal 21 (24): 6755–62. Dec 2002. doi:10.1093/emboj/cdf691. PMID 12485996. 
  20. ↑ 20.0 20.1 "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. Nov 2002. doi:10.1073/pnas.202608799. PMID 12438698. Bibcode: 2002PNAS...9915404K. 
  21. ↑ 21.0 21.1 21.2 "Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase". The Journal of Biological Chemistry 277 (24): 22085–92. Jun 2002. doi:10.1074/jbc.M201252200. PMID 11927591. 
  22. ↑ 22.0 22.1 22.2 "Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase". The Journal of Biological Chemistry 279 (30): 30919–22. Jul 2004. doi:10.1074/jbc.C400169200. PMID 15184379. 
  23. ↑ 23.0 23.1 "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. Sep 2003. doi:10.1074/jbc.C300249200. PMID 12890688. 
  24. ↑ 24.0 24.1 24.2 "BRCA1-independent ubiquitination of FANCD2". Molecular Cell 12 (1): 247–54. Jul 2003. doi:10.1016/S1097-2765(03)00281-8. PMID 12887909. 
  25. ↑ 25.0 25.1 "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. May 2001. doi:10.1074/jbc.C000881200. PMID 11278247. 
  26. ↑ 26.0 26.1 26.2 "The BARD1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression". Cell 104 (5): 743–53. Mar 2001. doi:10.1016/S0092-8674(01)00270-7. PMID 11257228. 
  27. ↑ 27.0 27.1 27.2 "Functional interaction of BRCA1-associated BARD1 with polyadenylation factor CstF-50". Science 285 (5433): 1576–9. Sep 1999. doi:10.1126/science.285.5433.1576. PMID 10477523. 
  28. ↑ "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. Aug 2002. PMID 12183411. 
  29. ↑ "Cancer susceptibility and the functions of BRCA1 and BRCA2". Cell 108 (2): 171–82. Jan 2002. doi:10.1016/S0092-8674(02)00615-3. PMID 11832208. 

Further reading



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