The DNA damage response in stem cell compartments and tissue homeostasis

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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.