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
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Choi, Su Mi; Kim, Yonghak; Shim, Joong Sup et al. (2013) Efficient drug screening and gene correction for treating liver disease using patient-specific stem cells. Hepatology 57:2458-68
Becherel, Olivier J; Yeo, Abrey J; Stellati, Alissa et al. (2013) Senataxin plays an essential role with DNA damage response proteins in meiotic recombination and gene silencing. PLoS Genet 9:e1003435
Laronda, Monica M; Unno, Kenji; Ishi, Kazutomo et al. (2013) Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium. Dev Biol 381:5-16
Chen, Shuyi; Li, Hua; Gaudenz, Karin et al. (2013) Defective FGF signaling causes coloboma formation and disrupts retinal neurogenesis. Cell Res 23:254-73
Deng, Changwang; Li, Ying; Liang, Shermi et al. (2013) USF1 and hSET1A mediated epigenetic modifications regulate lineage differentiation and HoxB4 transcription. PLoS Genet 9:e1003524
Haigis, Marcia C; Deng, Chu-Xia; Finley, Lydia W S et al. (2012) SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res 72:2468-72
Park, Seong-Hoon; Zhu, Yuming; Ozden, Ozkan et al. (2012) SIRT2 is a tumor suppressor that connects aging, acetylome, cell cycle signaling, and carcinogenesis. Transl Cancer Res 1:15-21
Lee, M-H; Lahusen, T; Wang, R-H et al. (2012) Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation. Oncogene 31:116-27
Xie, Yangli; Su, Nan; Jin, Min et al. (2012) Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia. Hum Mol Genet 21:3941-55
Kim, Eun-Hee; Deng, Chuxia; Sporn, Michael B et al. (2012) CDDO-methyl ester delays breast cancer development in BRCA1-mutated mice. Cancer Prev Res (Phila) 5:89-97

Showing the most recent 10 out of 32 publications