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    Research Grants Awarded

    Minor Recombination Pathways, Cellular Survival, And Tumorigenesis In The Absence Of BRCA2

    Study Section:
    Tumor Cell Biology V

    Scientific Abstract:
    (A) Background: Cellular survival and genomic integrity depends on the ability of cells to repair spontaneous DNA damage that arises in the course of every cell cycle. In particular, homologous recombination (HR) appears to be a key pathway for the repair of lesions such as double-strand breaks (DSBs) arising during DNA replication. Impaired HR and, as a result, high levels of spontaneous chromosome aberrations are associated with the hereditary breast cancer syndrome in women and men resulting from BRCA2 mutation have. BRCA2 interacts with and promotes the activity of the essential strand exchange protein Rad51. While loss of BRCA2 apparently causes cell lethality at embryonic stages as does loss of Rad51, its loss in somatic cell types like the mammary epithelium does not appear to cause cell lethality but rather to predispose to tumorigenesis. (B) Objectives/Hypotheses: We hypothesize that other recombination pathways are able to compensate for loss of BRCA2 in somatic cell types which permit the survival of these cells. In particular, Rad52 and Rad54, which are key HR proteins in yeast but normally minor players in mammalian HR, will be tested to determine if they contribute to an essential back-up pathway in the absence of BRCA2. (C) Specific aims: (1) To determine whether loss of Rad52 or Rad54 leads to significantly impaired DNA repair in BRCA2-deficient mammary tumors. (2) To determine whether loss of Rad52 or Rad54 compromises mammary tumor formation in a BRCA2 conditional mouse model. (3) To determine whether loss of Rad52 or Rad54 compromises viability of mice carrying a partially compromised (i.e., hypomorphic) allele of Brca2. (D) Study design: (1) We will characterize DNA repair in BRCA2-deficient mouse mammary tumor cells and determine whether Rad52 or Rad54 loss has a synergistic effect on DNA repair deficiency. (2) We will construct Rad52 and Rad54 mutant mice which can undergo conditional inactivation of Brca2 and determine whether tumor formation is affected compared with conditional inactivation of Brca2 alone. (3) We will construct Rad52/Brca2 and Rad54/Brca2 mice and assess embryonic and post-natal survival. (E) Potential outcomes/Benefits: These studies will lead to an understanding of the impact of ordinarily minor recombination pathways in BRCA2-deficient tumors. Should we uncover an important role for these minor recombination pathways, they have the potential to be an Achilles heel for these tumors.

    Lay Abstract:
    (A) Background: The survival of cells and the integrity of the genome depends on the ability of cells to repair DNA damage that arises by chance throughout the lifespan of a cell. The hereditary breast cancer susceptibility gene BRCA2 when mutated predisposes to breast cancer in both women and men. The predisposition is believed to arise because BRCA2 mutant cells are not able to properly repair DNA, making them susceptible to acquiring mutations in cancer causing genes. BRCA2 does not exist in model scientific organisms like yeast. Rather other proteins such as Rad54 and especially Rad52 are suspected to take its place. Nevertheless, the Rad52 and Rad54 proteins also exist in human cells but only seem to play a minor role in DNA repair. (B) Objectives/Hypotheses: We hypothesize that when tumor cells are deficient for BRCA2, minor DNA repair proteins become much more important. In particular, Rad52 and Rad54 may become essential to repair DNA damage that occurs. (C) Specific aims: (1) To determine whether loss of the minor DNA repair proteins Rad52 or Rad54 leads to significantly impaired DNA repair in BRCA2-deficient mammary tumors. (2) To determine whether loss of Rad52 or Rad54 compromises mammary tumor formation in a BRCA2 mouse model. (3) To determine whether loss of Rad52 or Rad54 compromises viability of mice carrying a partially compromised form of Brca2. (D) Study design: (1) We will characterize DNA repair in BRCA2-deficient mouse mammary tumor cells and determine whether Rad52 or Rad54 loss has a synergistic effect on DNA repair deficiency. (2) We will construct Rad52 and Rad54 mutant mice which can undergo conditional inactivation of Brca2 and determine whether tumor formation is affected compared to Brca2 inactivation alone. (3) We will construct Rad52/Brca2 and Rad54/Brca2 mice and assess embryonic and post-natal survival. (E) Potential outcomes/Benefits: These studies will lead to an understanding of the impact of ordinarily minor DNA repair pathways in BRCA2-deficient tumors. Should we uncover an important role for these minor recombination pathways, they have the potential to be an Achilles heel for these tumors.