Atm

The ataxia telangiectasia mutated gene (Atm) encodes for a kinase that phosphor-ylates a number of substrates in response to DNA damage. The same was found to be mutated in the rare autosomal-recessive disease ataxia telangiectasia (AT), a syndrome characterized by accelerated telomere loss, genomic instability, neurodegeneration, immunodeficiency, predisposition to malignancy, clinical radiosensi-tivity, and incomplete sexual maturation (Shiloh 2003). The phenotype observed in these patients was in part recapitulated in a number of knockout mice generated for Atm (Barlow et al. 1996, Elson et al. 1996, Xu et al. 1996).

Atm itself has a role in maintaining length and function of telomere in yeast and mammalian cells (Vaziri et al. 1997, Hande et al 2001, Greenwell et al 1995, Naito 1998). In addition, various studies have shown that Atm contributes to DNA damage signals induced by telomere dysfunction (d'Adda di Fagagna 2003). Atm deficiency in Terc mice leads to an acceleration of telomere shortening associated with a general proliferation defect on stem and progenitor cells levels also affecting neuronal stem cells (Wong et al. 2003). The life span of double mutant mice is significantly shorter than that of late-generation Terc mice. However, there was substantial elimination of T cell lymphoma associated with Atm deficiency in Terc_/" mice. Reduced life span of Terc"'", Atm~'~ mice correlates with an aggravation of defects in organ maintenance occurring in Terc~'~ knockout mice. Together, these results indicate that Atm-independent pathways can mediate the activation of DNA damage signals in telomere dysfunctional mice. The aggravation of organ phenotypes in Terc"/", Atm"/" double knockout mice is presumably due to the role of Atm in maintaining telomere length and function (see above), adding up to the level of telomere dysfunction in Tercmice. In addition, Atm appears to play a role in detoxification of reactive oxygen species (ROS). In Terc+/+ mice, Atm deletion induces bone marrow failure characterized by an impaired repopulating capacity of Atm~'~ HSC and elevated levels of ROS and p16Ink4a in the HSC compartment (Ito 2004). The loss of HSC function in Atm~'~ mice could not be rescued by overexpression of telomerase (Ito et al. 2006), indicating that telomere-independent functions of Atm are required for the maintenance of stem cell function.

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How To Deal With Rosacea and Eczema

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