The DNA damage response in stem cell compartments and tissue homeostasis

细胞内的基因组不断受到DNA损伤剂的挑战。每个细胞都有DNA损伤反应（DDR），包括DNA修复、细胞周期检查点和细胞凋亡，主要由两种蛋白激酶ATM和ATR调控。缺乏DDR与组织变性、过早衰老和疾病有关。DDR通路中的关键组分如ATM、ATR、MRE 11和NBS 1的突变分别引起共济失调-毛细血管扩张症（A-T）、Seckel综合征、A-T样障碍（A-T）和奈梅亨断裂综合征（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对于维持干细胞命运，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。干细胞功能的维持对于组织内稳态以防止组织萎缩、过早衰老和癌症是必不可少的。已经充分确定，MRN复合物（NBS 1/MRE 11/RAD 50）或ATR中的无效突变导致细胞致死。然而，我们最近发现在DFG支持的最后一段时间内，Nbs 1的缺失导致了几种组织中干细胞的短暂爆发，随后是干细胞库的加速耗尽。这些新的和令人惊讶的发现导致我们提出以下研究：（1） 研究在体内早期DDR分子耗尽后引起干细胞和反应性细胞类型快速但短暂爆发的机制。（二） 为了研究Nbs 1在细胞核和非典型胞浆中的功能以及DDR在干细胞维持和组织稳态中的作用，我们拟采用Nbs 1条件性基因敲除模型来描述DDR网络在维持干细胞活性和组织稳态中的作用。这些研究将有助于了解DDR在神经退行性疾病发展中的作用，并为过早衰老和年龄相关发病机制提供见解。

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.