Pathway Map Details

DNA damage_Role of Brca1 and Brca2 in DNA repair



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MSH6, Rad50, Brca1, ATR, MSH2, MSH3, Brca1/Bard1, FANCL, MRE11, NTH1, ATF-1, Nibrin, Brca2, RNA polymerase II, p53BP1, ATM, Rad51, NFBD1, PCNA, Histone H2AX, XPC, BRIP1, MLH1, Chk2, p53, DDB2, FANCD2, Bard1, DNA polymerase beta, MRN complex

Description:

Role of Brca1 and Brca2 in DNA Repair

DNA damage-dependent activation of the breast and ovarian cancer susceptibility protein 1 ( Brca1 ) occurs via activation of ataxia telangiectasia mutated serine-protein kinase ( ATM ) [1] or ataxia telangiectasia and Rad3 related protein kinase ( ATR ) [2]. These kinases phosphorylate Brca1 directly or indirectly (via cell cycle checkpoint kinase 2 ( Chk2 ) [3] ). Phosphorylated by ATM and ATR histones ( H2AX ) are co-localized together with some proteins to form nuclear foci at DNA damage sites. The loci can include the tumor protein 53-binding protein, 1 ( 53BP1 ) and the nuclear factor with BRCT domians protein 1 ( NFBD1 ), which take part in activation of Chk2 [4], MRN complex (consisting from double-strand break repair protein ( Mre11 ), Rad50 homolog (S. cerevisiae) ( Rad50 ) and Nijmegen breakage syndrome 1 protein ( Nibrin )) is a part of these foci, as well.

One suggested response of Brca1 to DNA damage consists of monoubiquitination of H2AX, followed by remodeling the chromatin in such a way that damaged DNA becomes assessable to the DNA repair machinery [5]. E3 ubiquitin ligase activity of Brca1 considerably amplifies, if Brca1 forms a complex with a Brca1 associated RING domain protein 1 ( BARD1 ) [6].

Brca1 plays a central role in DNA repair by facilitating cellular response to DNA repair. There are numerous DNA repair pathways directed to the specific types of damage, and a given type of damage can be targeted by several pathways. Major DNA repair pathways are mismatch repair (MMR), nucleotide excision repair (NER), base excision repair (BER), homologous recombinational repair (HRR), and non-homologous end joining (NHEJ) [7].

Brca1 participates in all these pathways.

Participation Brca1 in NER is mediated by transcription factors p53 and SP1. These TFs activate transcription of damage-specific DNA binding protein 2 ( DDB2 ) and xeroderma pigmentosum group C protein ( XPC ). In addition, activated by Brca1, p53 participates in BER by exciting transcription of proliferating cell nuclear antigen ( PCNA ) and stimulating activity of the endonuclease III-like 1 enzyme ( Nth1 ).

Moreover, Brca1 seems to be involved in DNA repair processes such as transcription-coupled repair (TCR) via activation of RNA polymerase II transcription machinery [8], [9].

Both Brca1 and Brca2 are implicated in HRR via DNA repair protein, S.cerevisiae homolog RAD51. RAD51 is a key component of the mechanism in which DNA damage is repaired by homologous recombination [10]. Moreover, Brca1 may activate Brca1 interacting protein C-terminal helicase 1 ( BRIP1 ) [11]. BRIP1 is able to catalytically release the third strand of the homologous recombination intermediate D-loop structure irrespective of DNA tail status [12].

It is shown that Fanconi anemia complementation group D2 protein, isoform 1 ( FANCD2 ) (in a complex with RAD51 and/or Brca s) participates in HRR [13]. At the same time, FANCD2 should be ubiquitinated (by a complex of Fanconi anemia proteins ( FANC complex ), for example) [14]. Moreover, Fanconi anemia proteins/ Brca1 pathway participates in DNA interstrand cross-link (ICL) repair [15].

Role of Brca1 in NHEJ consists of regulation of the MRN complex. Phosphorylated by Chk2, Brca1 inhibits Mre11. It depresses NHEJ pathway and stimulates HRR RAD51 -dependent pathway [3]. In addition, Brca1 may stimulate HRR and NHEJ via activation of Rad50 [16], [17].

Brca1 and BARD1 are downstream effectors of the adenosine nucleotide-activated DNA mismatch repair protein signaling complex ( MSH2, MSH3, MSH6, MLH1 ), and suggest a global role for Brca1 in MMR [18]. It is shown, that p53 take part of MMR [19].

References:

  1. Cortez D, Wang Y, Qin J, Elledge SJ
    Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 1999 Nov 5;286(5442):1162-6
  2. Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT
    Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes & development 2000 Dec 1;14(23):2989-3002
  3. Zhang J, Willers H, Feng Z, Ghosh JC, Kim S, Weaver DT, Chung JH, Powell SN, Xia F
    Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Molecular and cellular biology 2004 Jan;24(2):708-18
  4. Peng A, Chen PL
    NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage. The Journal of biological chemistry 2003 Mar 14;278(11):8873-6
  5. Chen A, Kleiman FE, Manley JL, Ouchi T, Pan ZQ
    Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase. The Journal of biological chemistry 2002 Jun 14;277(24):22085-92
  6. Xia Y, Pao GM, Chen HW, Verma IM, Hunter T
    Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein. The Journal of biological chemistry 2003 Feb 14;278(7):5255-63
  7. Fleck O, Nielsen O
    DNA repair. Journal of cell science 2004 Feb 1;117(Pt 4):515-7
  8. Gowen LC, Avrutskaya AV, Latour AM, Koller BH, Leadon SA
    BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 1998 Aug 14;281(5379):1009-12
  9. Le Page F, Randrianarison V, Marot D, Cabannes J, Perricaudet M, Feunteun J, Sarasin A
    BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer research 2000 Oct 1;60(19):5548-52
  10. Shin DS, Pellegrini L, Daniels DS, Yelent B, Craig L, Bates D, Yu DS, Shivji MK, Hitomi C, Arvai AS, Volkmann N, Tsuruta H, Blundell TL, Venkitaraman AR, Tainer JA
    Full-length archaeal Rad51 structure and mutants: mechanisms for RAD51 assembly and control by BRCA2. The EMBO journal 2003 Sep 1;22(17):4566-76
  11. Shiozaki EN, Gu L, Yan N, Shi Y
    Structure of the BRCT repeats of BRCA1 bound to a BACH1 phosphopeptide: implications for signaling. Molecular cell 2004 May 7;14(3):405-12
  12. Gupta R, Sharma S, Sommers JA, Jin Z, Cantor SB, Brosh RM Jr
    Analysis of the DNA substrate specificity of the human BACH1 helicase associated with breast cancer. The Journal of biological chemistry 2005 Jul 8;280(27):25450-60
  13. Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD
    S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood 2002 Oct 1;100(7):2414-20
  14. Nakanishi K, Yang YG, Pierce AJ, Taniguchi T, Digweed M, D'Andrea AD, Wang ZQ, Jasin M
    Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair. Proceedings of the National Academy of Sciences of the United States of America 2005 Jan 25;102(4):1110-5
  15. Rothfuss A, Grompe M
    Repair kinetics of genomic interstrand DNA cross-links: evidence for DNA double-strand break-dependent activation of the Fanconi anemia/BRCA pathway. Molecular and cellular biology 2004 Jan;24(1):123-34
  16. Somasundaram K
    Breast cancer gene 1 (BRCA1): role in cell cycle regulation and DNA repair--perhaps through transcription. Journal of cellular biochemistry 2003 Apr 15;88(6):1084-91
  17. Zhong Q, Boyer TG, Chen PL, Lee WH
    Deficient nonhomologous end-joining activity in cell-free extracts from Brca1-null fibroblasts. Cancer research 2002 Jul 15;62(14):3966-70
  18. Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene MI
    Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1. Oncogene 2001 Aug 2;20(34):4640-9
  19. Zink D, Mayr C, Janz C, Wiesmuller L
    Association of p53 and MSH2 with recombinative repair complexes during S phase. Oncogene 2002 Jul 18;21(31):4788-800