The DNA damage response in stem cell compartments and tissue homeostasis

细胞内的基因组不断受到dna损伤因子的挑战。每个细胞都存在DNA损伤反应（DDR），包括DNA修复、细胞周期检查点和细胞凋亡，DDR主要由两种蛋白激酶ATM和ATR控制。缺乏DDR与组织变性、早衰和疾病有关。DDR通路中关键组分ATM、ATR、MRE11和NBS1的突变分别导致共济失调-毛细血管扩张症（A-T）、Seckel综合征、A-T样疾病（A-TLD）和奈梅根断裂综合征（NBS）。这些疾病的主要症状重叠，包括共济失调、小头畸形、免疫缺陷、染色体不稳定和癌症易感性。最近的研究，包括我们的研究，表明DDR对维持干细胞命运、组织稳态和衰老至关重要。干细胞在人的一生中提供各种类型的功能性体细胞。干细胞功能的维持是维持组织稳态，防止组织萎缩、早衰和癌变的必要条件。已经确定MRN复合物（NBS1/MRE11/RAD50）或ATR中的零突变会导致细胞死亡。然而，我们最近发现，在DFG支持的最后阶段，Nbs1的缺失会导致几个组织中干细胞的短暂爆发，随后是干细胞库的加速耗尽。这些令人惊讶的新发现促使我们提出以下研究：(1)研究在早期DDR分子耗尽后，体内干细胞和反应性细胞类型快速但短暂爆发的机制。(2)研究Nbs1在细胞核和非典型细胞质中的功能，以及DDR在干细胞维持和组织稳态中的作用。我们建议使用Nbs1条件敲除模型来描述DDR网络在维持干细胞能力和适当的组织稳态中的作用。这些研究将有助于了解DDR在神经退行性疾病发展中的功能，并为过早衰老和年龄相关的发病机制提供见解。

The genome within the cell is constantly being challenged by DNA-damaging agents. Every cell is equipped with the DNA damage response (DDR), consisting of DNA repair, cell cycle checkpoint and apoptosis, which are governed mainly by two protein kinases ATM and ATR. Deficient DDR is associated with tissue degeneration, premature aging and diseases. Mutations of key components in the DDR pathways, such as ATM, ATR, MRE11 and NBS1, cause Ataxia-Telangiectasia (A-T), Seckel Syndrome, A-T Like Disorder (A-TLD) and Nijmegen Breakage Syndrome (NBS), respectively. The major symptoms overlap in these diseases ranging from ataxia, microcephaly, immunodeficiency, chromosomal instability and cancer susceptibility. Recent studies, including ours, indicate that DDR is vital for the maintenance of stem cell fate, tissue homeostasis and aging. Stem cells supply various types of functional somatic cells throughout a lifetime. The maintenance of the stem cell functionality is essential for the tissue homeostasis to prevent tissue atrophy, premature aging and cancer. It has been well established that null mutation in the MRN complex (NBS1/MRE11/RAD50) or in ATR causes cell lethality. However, we recently found during the last period of DFG support that a deletion of Nbs1 caused a transient burst of stem cells in several tissues, followed by an accelerated exhaustion of stem cell pools. These new and surprising findings lead us to propose the following studies:(1) To investigate the mechanism that caused a rapid, but transient, burst of stem cells and reactive cell types in vivo after a depletion of the early DDR molecule. (2) To study the function (nuclear and non-canonical cytoplasmic) of Nbs1 and the link of DDR in stem cell maintenance and tissue homeostasis.We propose to use Nbs1 conditional knockout model to delineate the DDR network in the maintenance of stem cell competence and proper tissue homeostasis. These studies will help understanding the function of DDR in the development of neurodegenerative diseases and provide insights into premature aging and age-related pathogenesis.