BRCA2 by ert554898


By Jordan Masterson
March 21, 2006
A little bit about breast
   1 in every 8 women
   10% exhibit the
    familial pattern of
   30-50% of familial
    cases involve a
    mutation in BRCA1
    or BRCA2

   Similarities?
   Differences?

Simon N. Powell and Lisa A. Kachnic

 Marroni et al.
Role of BRCA2

    “…Major biological function is the
     maintenance of chromosome structure
     stability in dividing cells by regulation
     of steps in recombination by
     homologous DNA strands.”1
    “…Facilitate orderly homologous
     recombination and thereby maintain
     genomic integrity.”2
    1Luca Pellegrini and Ashok Venkitaraman
    2Simon N. Powell and Lisa A Kachnic
DNA repair

   2 mechanisms to repair double-strand
    – Non-homologous End Joining (NHEJ)
    – Homologous Recombination (HR)
        Gene conversion
        Single strand annealing
          BRCA2 + RAD51

Simon N. Powell and Lisa A. Kachnic
In Mouse Models and
Human Case studies…
   BRCA2 null
    embryos in mice


   Human
    Carrier Analyses

                       Arnold, K et al.
How does BRCA2 cause
   Decreases the amount of
    proper/effective DNA repair
   Increases Genomic Instability
Why breast cancer?

   “Heterozygous germline mutations in
    BRCA2 predispose carriers
    predominantly to breast and ovarian
    cancers…the relationship between
    genotype and phenotype in BRCA2
    mutated cells is complex, e.g. an
    identical mutation can be associated
    with different cancer phenotypes.”3
    3Arnold,   K., et al.
   Pellegrini, Luca and Ashok Venkitaraman. “Emerging
    functions of BRCA2 in DNA recombination.” TRENDS in
    Biochemical Sciences 29.6 (2004): 310-316.
   Powell, Simon N. and Lisa A. Kachnic. “Roles of BRCA1 and
    BRCA2 in homologous recombination, DNA replication fidelity,
    and the cellular response to ionizing radiation.” Oncogene 22
    (2003): 5784-5791.
   Arnold, K. et al. “Lower level of BRCA2 protein in
    heterozygous mutation carriers is correlated with an increase
    in DNA double strand breaks and an impaired DSB repair.”
    Cancer Letters (2006): 1-11.
   Kim, MK et al. “Increased rates of spontaneous sister
    chromatid exchange in lymphocytes of BRCA2+/- carriers of
    familial breast cancer clusters.” Cancer Letters 210.1 (2004)
References, con’t
   Tutt, A. et al. “Mutation in BRCA2 stimulates error-prone
    homology-directed repair of DNA double-strand breaks
    occurring between repeated sequences.” EMBO Journal 20.17
    (2001): 4704-4716.
   Jonkers, Jos et al. “Synergistic tumor suppressor activity of
    BRCA2 and p53 in a conditional mouse model for breast
    cancer.” Nature Genetics 29 (2001): 418-425.
   Marroni, F. et al. “Penetrances of breast and ovarian cancer
    in large series of families tested for BRCA1/2 mutations.”
    European Journal of Human Genetics 12.11 (2004): 901.
 _images/lab_mouse140.jpg

To top