Abstract：
:Developmental abnormalities, cancer, and premature aging each have been linked to defects in the DNA damage response (DDR). Mutations in the ATR checkpoint regulator cause developmental defects in mice (pregastrulation lethality) and humans (Seckel syndrome). Here we show that eliminating ATR in adult mice leads to defects in tissue homeostasis and the rapid appearance of age-related phenotypes, such as hair graying, alopecia, kyphosis, osteoporosis, thymic involution, fibrosis, and other abnormalities. Histological and genetic analyses indicate that ATR deletion causes acute cellular loss in tissues in which continuous cell proliferation is required for maintenance. Importantly, thymic involution, alopecia, and hair graying in ATR knockout mice were associated with dramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity. In aggregate, these studies suggest that reduced regenerative capacity in adults via deletion of a developmentally essential DDR gene is sufficient to cause the premature appearance of age-related phenotypes.
journal_name
Cell Stem Celljournal_title
Cell stem cellauthors
Ruzankina Y,Pinzon-Guzman C,Asare A,Ong T,Pontano L,Cotsarelis G,Zediak VP,Velez M,Bhandoola A,Brown EJdoi
10.1016/j.stem.2007.03.002subject
Has Abstractpub_date
2007-06-07 00:00:00pages
113-26issue
1eissn
1934-5909issn
1875-9777pii
S1934-5909(07)00005-7journal_volume
1pub_type
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