Our earlier studies indicated that genetic instability associated with BRCA1 deficiency activates the DNA damage response (DDR) and thereby causes growth arrest and/or apoptosis. Analyzing Brca1(delta11/delta11)p53+/- mice, we found that the absence of full-length BRCA1 caused senescence in mutant embryos and cultured cells as well as aging and tumorigenesis in adult mice. Haploid loss of p53 overcame embryonic senescence but failed to prevent the adult mutant mice from prematurely aging, characterized by decreased life span, reduced body fat deposition, osteoporosis, skin atrophy and decreased wound healing. We further demonstrated that mutant cells that escaped senescence had undergone clonal selection for faster proliferation and extensive genetic/ molecular alterations including the loss of p53. These observations provide the first in vivo evidence that links cell senescence to aging due to impaired tumor suppression function of BRCA1 and activation of p53. However the factors responsible for p53 activation in the absence of Brca1 are poorly understood. To investigate this, in the past year, we employed a genetic test by crossing Brca1(delta11/+) mice with mutant mice carrying targeted mutations of genes in the DDR pathway, including 53BP1, ATM, Chk1, Chk2, p19, Pten, Parp-1, p21 and Gadd45. Our data indicated that 53BP1, ATM or Chk2 inactivation is equivalent to p53 inactivation in that it abolishes DDR and allows Brca1(delta11/delta11) embryos to survive to adulthood. These observations support a model indicating that BRCA1 deficiency results in genetic instability, leading to the activation of 53BP1-ATM-Chk2-p53 DDR signaling, which, in turn, serves as a natural barrier against malignant transformation of BRCA1 mutant cells. We show that reduced expression and/or the absence of Chk2 allow Brca1(delta11/delta11) mice to escape from embryonic lethality. Compared to Brca1(delta11/delta11)p53+/- mice, lifespan of Brca1(delta11/delta11)Chk2-/- mice was remarkably extended. Analysis of Brca1(delta11/delta11)Chk2-/- mice revealed that p53-dependent apoptosis and growth defect caused by Brca1 deficiency are significantly attenuated in rapidly proliferating organs. However, in later life, Brca1(delta11/delta11)Chk2-/- female mice developed multiple tumors. Furthermore, haploid loss of ATM also rescued Brca1 deficiency-associated embryonic lethality and premature aging. Thus, in response to Brca1 deficiency, the activation of the ATM-Chk2-p53 signaling pathway contributes to the suppression of neoplastic transformation, while leading to compromised organismal homeostasis. Our data highlight how accurate maintenance of genomic integrity is critical for the suppression of both aging and malignancy, and provide a further link between aging and cancer.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$1,047,427
Indirect Cost
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State
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