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BRCA1 Pathway

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The maintenance of genome integrity is essential to all life, but is particularly important to long-lived multicellular organisms, which are susceptible to cancer. DNA damage can take the form of base modifications, strand breaks, interstrand cross-links and other lesions. To deal with many types of damage, genomes have evolved multiple cellular defense mechanisms, including DNA repair and cell cycle checkpoint processes. Different pathways exist for specific kinds of DNA damage and the cell must have ways to decide which mechanism to use for a given lesion. These requirements imply that signaling networks not only sense the presence of DNA damage, but also receive specific input such as the chemical nature of the damage, the timing of the cell cycle, the type of cell and the location of damage on the DNA. BASC (BRCA1-Associated Genome Surveillance Complex), a super complex of BRCA1 (Breast Cancer Susceptibility Protein-1), is key to recognizing and repairing DNA damage. This complex includes tumor suppressors and DNA damage repair proteins MSH2, MSH6, MLH1, ATM (Ataxia-Telangiectasia), BLM (Bloom syndrome), and the Rad50-MRE11 (Meiotic Recombination-11)-NBS1 (Nijmegen Breakage Syndrome) protein complex. In addition, RFC (DNA Replication Factor-C), a protein complex that facilitates the loading of PCNA onto DNA, is also part of BASC (Ref.1 & 2).

Eleven or more genetically distinct groups of FA have been described (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCG, FANCE, FANCF and FANCL), each caused by recessive mutations in a different gene (Ref.4, 5 & 6). DNA damage activates the monoubiquitylation of FANCD2 (Fanconi Anemia subtype D2 protein), which is targeted to subnuclear foci, where it co-localizes with BRCA1 and Rad51 (Ref.3). FA (Fanconi Anemia) is genetically heterogeneous, with at least eleven or more genetically distinct groups (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG and FANCL), each caused by recessive mutations in a different gene (Ref.4, 5 & 6) (Ref.3). Five of the proteins (FANCA, FANCC, FANCE, FANCF and FANCG) assemble in a multisubunit nuclear complex required for the activation of FANCD2 to a monoubiquitinated isoform (FANCD2-Ub), either in response to DNA damage or during S-Phase of the Cell Cycle, thereby targeting FANCD2 to DNA repair nuclear foci containing BRCA1, BRCA2 and Rad51, which are important in maintaining genomic stability by promoting homologous recombination repair (Ref.7). BRCA1 is a nuclear phosphoprotein, which interacts with Rad51, a human homolog of RecA, and with the Rad50-MRE11-NBS1 complex. In living cells, BRCA1 exists mostly as a heterodimeric complex with BARD1 (BRCA1-Associated RING Domain-1). BARD1 is involved in BRCA1-mediated tumor suppression. BRCA1-BARD1 co-localizes with DNA replication and repair factors in response to DNA damage. BRCA1-BARD1 heterodimers exhibit significant E3 Ub Ligase activity and the BARD1 RING finger domain greatly potentiates the Ligase activity of the BRCA1 RING finger (Ref.8). The ATM and ATR (ATM and Rad3 related) kinases, both implicated in responses to genotoxic stress, are also involved for the radiation-induced phosphorylation of BRCA1 (Ref.9). Normally, ATM phosphorylates Chk2 (Chk1 Checkpoint Homolog), which in turn phosphorylates BRCA1. The ring finger of BRCA1 confers ubiquitin ligase activity that is markedly enhanced when complexed with another ring-containing protein, BARD1 (BRCA1 Associated Ring Domain-1), and is required for the function of this tumor suppressor protein in protecting genomic integrity (Ref.10). ATR and ATM kinase targets also include repair enzymes like Rad51, Chk1 and Chk2. In response to ionizing radiation, ATM phosphorylates NBS1 leading to phosphorylation of FANCD2 and the establishment of an S-Phase checkpoint response, and in response to Mitomycin-C or Hydroxyurea, NBS1 assembles in nuclear foci with MRE11-Rad50 and FANCD2. Like ATM, the MRE11 complex is a crucial upstream regulator of checkpoint responses and DNA-repair responses in all eukaryotic cells. The MRE11 complex assembles with BRCA1 in nuclear foci following DNA damage and regulate homologous recombination repair (Ref.11). BRCA2 functions upstream in the pathway by promoting FA-complex assembly and FANCD2 activation, and/or downstream by transducing signals from FA proteins to Rad51.

BRCA1 has also been implicated in gene regulation. It induces GADD45, a p53-regulated and stress-inducible gene that plays an important role in cellular response to DNA damage. BRCA1 activation of the GADD45 promoter is mediated through the OCT1 and CAAT motifs located at the GADD45 promoter region (Ref.12). BRCA1 can trigger a G1 arrest that is mediated by transcriptional activation of p21Waf1/Cip1. In addition to its association with holoenzyme, BRCA1 can bind to several different transcription factors, including p53, Myc, STAT1, and CtIP (CBP-Interacting Protein) (Ref.13). BRCA1 acts in concert with STAT1 to differentially activate transcription of a subset of IFN-Gamma target genes and mediates growth inhibition by this cytokine. BRCA1 also binds preferentially to the hypophosphorylated form of Rb (Retinoblastoma Protein) (Ref.14). The carboxy-terminal region of the tumor suppressor protein BRCA1 is a functionally significant domain. CtIP, interacts specifically with the carboxy-terminal segment of BRCA1 from residues 1602-1863 but the exact function of CtIP is unknown. The C-terminal domain of BRCA1 (BRCT) activates transcription and interacts with RNA Polymerase holoenzyme. The BRCA1 RING finger associates with ATF1, a member of the cAMP response element-binding protein/activating transcription factor (CREB/ATF) family and leads to transcriptional activation of ATF1 target genes, some of which are involved in the transcriptional response to DNA damage (Ref.13). DNA repair by homologous recombination is mediated by the BRCA1-associated surveillance complex (comprised of BLM, MSH2–MSH6 and MRE11–Rad50–NBS1). BRCA1 can form complexes with both BACH1 and SWI/SNF to mediate chromatin remodeling and homologous recombination. HDACs regulate the access of the SWI/SNF–BRCA1 complex to DNA. Finally, BRCA1 interacts with Chk1 and PLK1 (Polo-Like Kinase-1) to regulate the G2/M and G1/S checkpoints, possibly via GADD45; thereby linking BRCA1 to the regulation of apoptosis.

BRCA1 is a tumor suppressor gene implicated in the predisposition to early onset breast and ovarian cancer. Loss of the tumor suppressor BRCA1 results in profound chromosomal instability. As a tumor suppressor, BRCA1 exerts a pleiotropic effect, playing a role in the maintenance of genomic integrity. Several functions have also been ascribed to BRCA1 including double strand DNA break repair, participating in genome surveillance, transcription-coupled DNA repair, transcriptional regulation, chromatin remodeling, and ubiquitin ligation and cell cycle checkpoint arrests. In cells, loss of BRCA1 function leads to spontaneous chromosome breakage and sensitivity to DNA damage (Ref.15).

References:
  1. Grompe M
    FANCD2: a branch-point in DNA damage response?
    Nat. Med. 2002 Jun;8(6): 555-6.
  2. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J
    BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.
    Genes Dev. 2000 Apr 15;14(8):927-39.
  3. Pang Q, Keeble W, Christianson TA, Faulkner GR, Bagby GC
    FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity.
    EMBO J. 2001 Aug 15; 20(16): 4478-89.
  4. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD
    Biallelic inactivation of BRCA2 in Fanconi anemia.
    Science. 2002 Jul 26; 297(5581): 606-9.
  5. Taniguchi T, D'Andrea AD
    Molecular pathogenesis of Fanconi anemia: recent progress.
    Blood. 2006 Jun 1;107(11):4223-33.
  6. Levitus M, Rooimans MA, Steltenpool J, Cool NF, Oostra AB, Mathew CG, Hoatlin ME, Waisfisz Q, Arwert F, de Winter JP, Joenje H
    Heterogeneity in Fanconi anemia: evidence for 2 new genetic subtypes.
    Blood. 2004 Apr 1;103(7):2498-503.
  7. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD
    Biallelic inactivation of BRCA2 in Fanconi anemia.
    Science. 2002 Jul 26; 297(5581): 606-9.
  8. Xia Y, Pao GM, Chen HW, Verma IM, Hunter T
    Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein.
    J. Biol. Chem. 2003 Feb 14;278(7):5255-63. Epub 2002 Nov 12.
  9. Foray N, Marot D, Randrianarison V, Venezia ND, Picard D, Perricaudet M, Favaudon V, Jeggo P
    Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation.
    Mol. Cell Biol. 2002 Jun; 22(12): 4020-32.
  10. Chen A, Kleiman FE, Manley JL, Ouchi T, Pan ZQ
    Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase.
    J. Biol. Chem. 2002 Jun 14; 277(24): 22085-92. Epub 2002 Apr 01.
  11. D'Andrea AD, Grompe M
    The Fanconi anaemia/BRCA pathway.
    Nat. Rev. Cancer. 2003 Jan; 3(1): 23-34.
  12. Fan W, Jin S, Tong T, Zhao H, Fan F, Antinore MJ, Rajasekaran B, Wu M, Zhan Q
    BRCA1 regulates GADD45 through its interactions with the OCT-1 and CAAT motifs.
    J. Biol. Chem. 2002 Mar 8;277(10):8061-7. PubMed ID: 11777930
  13. Aprelikova ON, Fang BS, Meissner EG, Cotter S, Campbell M, Kuthiala A, Bessho M, Jensen RA, Liu ET
    BRCA1-associated growth arrest is RB-dependent.
    Proc. Natl. Acad. Sci. U S A. 1999 Oct 12;96(21):11866-71.
  14. Mallery DL, Vandenberg CJ, Hiom K
    Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains.
    EMBO J. 2002 Dec 16; 21(24): 6755-62.