BRCA1, DNA damage response and aging

BRCA1、DNA 损伤反应和衰老

基本信息

批准号：
8741510
负责人：
Chuxia Deng
金额：
$ 104.74万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8741510
关键词：
ATM activation Acute Adult Aging Apoptosis Atrophic condition of skin Attenuated Body fat Cell Aging Cells DNA Damage Data Defect Deposition Elderly Embryo Female Gene Activation Gene Mutation Genes Genetic Genetic screening method Genome Genomics Growth Haploidy Homeostasis Human Knock-out Length Link Longevity Maintenance Malignant - descriptor Malignant Neoplasms Mammary gland Modeling Molecular Genetics Mus Mutant Strains Mice Neoplastic Cell Transformation Oncogenes Organ Osteoporosis Pathway interactions Premature aging syndrome Proliferating Secondary to Signal Transduction Surface Tissues Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Wound Healing embryonic cell culture in vivo loss of function mutation malignant breast neoplasm mutant null mutation p53 Signaling Pathway prevent response senescence tumor tumorigenesis

项目摘要

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.

我们的早期研究表明，与BRCA1缺乏相关的遗传不稳定性激活了DNA损伤反应（DDR），从而导致生长停滞和/或凋亡。分析BRCA1（Delta11/delta11）p53 +/-小鼠，我们发现缺乏全长的BRCA1导致成年小鼠的突变胚和培养细胞以及衰老和肿瘤发生导致衰老。 p53的单倍体损失克服了胚胎衰老，但未能阻止成年突变小鼠过早衰老，其特征是寿命降低，体内脂肪沉积减少，骨质疏松症，皮肤萎缩和伤口愈合降低。我们进一步证明，逃脱衰老的突变细胞经过克隆选择，以更快的增殖和广泛的遗传/分子改变，包括p53的丧失。这些观察结果提供了第一个体内证据，该证据将细胞衰老与BRCA1肿瘤抑制功能和p53激活相关引起的衰老。但是，在没有BRCA1的情况下，导致p53激活的因素知之甚少。为了调查这一点，在过去的一年中，我们通过将BRCA1（Delta11/+）小鼠与携带DDR途径中靶向突变的突变小鼠穿越基因检测，包括53BP1，ATM，CHK1，CHK1，CHK2，P19，P19，PTEN，PENP-1，PTEN，PENP-1，P21，P21和GADD45。我们的数据表明，53BP1，ATM或CHK2失活等于p53失活，因为它消除了DDR并允许BRCA1（Delta11/delta11）胚胎生存至成年。这些观察结果支持了一个模型，表明BRCA1缺乏会导致遗传不稳定性，从而导致53BP1-ATM-CHK2-P53 DDR信号的激活，这反过来又是反对BRCA1突变细胞的恶性转化的自然障碍。我们表明，CHK2的表达降低和/或允许BRCA1（Delta11/delta11）小鼠逃脱胚胎致死性。与BRCA1（delta11/delta11）p53 +/-小鼠相比，BRCA1（delta11/delta11）Chk2 - / - 小鼠的寿命非常扩展。 BRCA1（Delta11/delta11）CHK2 - / - 小鼠的分析表明，在快速增殖的器官中，由BRCA1缺乏引起的P53依赖性凋亡和生长缺陷显着减弱。但是，在后来的生活中，BRCA1（Delta11/delta11）CHK2 - / - 雌鼠患有多种肿瘤。此外，ATM的单倍体损失还挽救了BRCA1缺乏相关的胚胎致死性和过早衰老。因此，在响应BRCA1缺乏时，ATM-CHK2-P53信号通路的激活有助于抑制肿瘤转化，同时导致有机体稳态受损。我们的数据强调了基因组完整性的准确维持对于抑制衰老和恶性肿瘤至关重要，并在衰老和癌症之间提供了进一步的联系。