Disease relevance of Atm

• Patients with the human disorder ataxia-telangiectasia (A-T; refs 1,2) and Atm-deficient mice have a pleiotropic phenotype that includes infertility [1].
• Critical role for Atm in suppressing V(D)J recombination-driven thymic lymphoma [2].
• By introducing a RAG-1 deficiency into Atm-/- mice in the presence of a TCR transgene, we show that V(D)J recombination is critical for thymoma development in these mice [2].
• Moreover, DNA damage-induced apoptosis required the ataxia telangiectasia mutated (Atm) kinase after disruption of NHEJ, but not HR, during neurogenesis [3].
• Thymic lymphomas that developed in Rag2(-/-) Atm(-/-) mice contained multiple chromosomal abnormalities, but none of these involved the Tcr alpha/delta locus [4].

High impact information on Atm

• Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer [5].
• Atm is part of a pathway that responds to DNA damage from ionizing radiation (IR) [6].
• To determine the relationship between Atm and p53, we examined cell-cycle and apoptotic responses in Atm-, p53-(ref. 8) and p21-deficient mice after IR in the whole animal [6].
• As expected, p53 protein levels were not induced by IR in thymus of Atm-deficient mice [6].
• Here we demonstrate that male gametogenesis is severely disrupted in Atm-deficient mice in the earliest stages of meiotic prophase I, resulting in apoptotic degeneration [1].

Chemical compound and disease context of Atm

• Whereas ataxia telangiectasia-mutated (ATM) kinase normally represses ceramide synthase, its derepression in Atm(-/-) mice increased crypt stem cell radiosensitivity 3.7-fold without sensitizing the microvascular response [7].
• We tested this hypothesis by determining whether the well-described nitroxide antioxidant, tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), acts as a chemopreventative agent in Atm mutant mice, a model of the human cancer prone syndrome ataxia-telangiectasia [8].
• Prevention of thymic lymphoma development in Atm-/- mice by dexamethasone [9].
• Reduction of ROS by the antioxidant N-acetyl-l-cysteine (NAC) prevented the emergence of senescent phenotypes in Atm(-/-) mouse embryonic fibroblasts, hypersensitivity to total body irradiation, and thymic lymphomagenesis in Atm(-/-) mice [10].
• Here we show that Atm more broadly protects against both spontaneous and phenytoin-enhanced embryopathies [11].

Biological context of Atm

• Our results support a model in which upstream effectors such as Atm selectively activate p53 to regulate specific downstream pathways, providing a mechanism for controlling distinct cell-cycle and apoptotic responses [6].
• Furthermore, these data suggest that V(D)J recombination is a critical, but not essential, event during which Atm-deficient thymocytes are susceptible to developing chromosome aberrations that predispose to malignant transformation [12].
• These data are consistent with the hypothesis that the major mechanism of tumorigenesis in Atm(-/-) mice is via chromosomal translocations and other abnormalities that are secondary to aberrant responses to double-stranded DNA breaks [12].
• The increased CIN is manifested at the cellular level by increased chromatid breaks and elevated aneuploid genome in Atm-/- p21-/- cells [13].
• It was found that Atm-deficient cells are defective in metaphase-anaphase transition leading to abnormal karyokinesis [13].

Anatomical context of Atm

• The central nervous system (CNS) of Atm-null mice shows a pronounced defect in apoptosis induced by genotoxic stress, suggesting ATM functions to eliminate neurons with excessive genomic damage [14].
• The absence of ATM caused defects in folliculogenesis that were similar to those in Dmc1 mutants and that could be suppressed by Spo11 mutation, implying that oocyte death in Atm-deficient animals is a response to defective DSB repair [15].
• Mice deficient for Atm are male sterile with arrest and apoptosis occurring at testis epithelial stage IV, which in normal spermatocytes corresponds to mid-pachynema [16].
• These compound mutants showed increased telomere erosion and genomic instability, yet they experienced a substantial elimination of T-cell lymphomas associated with Atm deficiency [17].
• We show that Atm deficiency and telomere dysfunction act together to impair cellular and whole-organism viability, thus supporting the view that aspects of A-T pathophysiology are linked to the functional state of telomeres and its adverse effects on stem/progenitor cell reserves [17].

Associations of Atm with chemical compounds

• P53 was transiently phosphorylated at serine 23 during liver regeneration in an Atm-dependent manner [18].
• Effect of the reduction of superoxide dismutase 1 and 2 or treatment with alpha-tocopherol on tumorigenesis in Atm-deficient mice [19].
• We show that the Atm/Atr inhibitor 2-aminopurine causes the inactive X chromosome to accumulate abnormal chromatin and undergo unwanted gene reactivation [20].
• Discovery of this intestinal radiosensitivity mechanism allowed design of an antisense Atm oligonucleotide treatment which phenocopied the Atm(-/-) mouse, reordering ceramide synthase-mediated stem cell death to become the first-line gastrointestinal response of wild-type littermates [7].
• Behaviorally, Atm-deficient mice expressed locomotor abnormalities manifested as stride-length asymmetry, which could be corrected by peripheral application of the dopaminergic precursor L-dopa [21].

Regulatory relationships of Atm

• Taken together, our results support a model in which the upstream effectors DNA-PKcs and Atm selectively activate p53 to differentially regulate cell-cycle and apoptotic responses [22].
• Finally, we showed that the role of p21 in a CIN background induced by loss of Atm is to suppress numerical CIN but not structural CIN [13].
• We report here the lack of a mutator phenotype for inactivating autosomal mutations in solid tissues of the Atm-deficient mice [23].
• Surprisingly, mice in which the Atm gene has been inactivated lack distinct behavioral ataxia or pronounced cerebellar degeneration, the hallmarks of the human disease [21].

Other interactions of Atm

• In contrast to expectation, the data presented here indicate that development of malignant thymic lymphoma in Atm(-/-) mice is not prevented by loss of RAG-2 and thus is not dependent on V(D)J recombination [12].
• Here, we report that the death effector Bax is required for a large proportion of Atm-dependent apoptosis in the developing CNS after ionizing radiation (IR) [14].
• Atm-deficient mice die of malignant thymic lymphomas characterized by translocations within the Tcr alpha/delta locus, suggesting that tumorigenesis is secondary to aberrant responses to double-stranded DNA (dsDNA) breaks that occur during RAG-dependent V(D)J recombination [4].
• This temporal resolution suggests that Atm and p53 can act to maintain genomic integrity by different mechanisms in certain in vivo contexts [24].
• We conducted an in vivo examination of the frequency of spontaneous homologous recombination in Atm-, p53-, or Gadd45a-deficient mice [24].

Analytical, diagnostic and therapeutic context of Atm

• Using immunoprecipitation and immunoblot analysis, we show that Atr and Atm proteins are approximately 300 and 350 kD relative molecular mass, respectively, and further demonstrate that both proteins have associated protein kinase activity [25].
• Finally, we show that increased apoptosis was observed in Atm(-/-) mice in response to partial hepatectomy, indicating that Atm is required for the survival of hepatocytes [18].
• A murine model of ataxia telangiectasia was created by disrupting the Atm locus via gene targeting [26].
• Atm(-/-) cells in vivo, and in cell culture, show a blunted response to environmental stimuli that promote neural progenitor cell proliferation, survival, and differentiation along a neuronal lineage [27].
• To assess this hypothesis, we employed an animal model of A-T, the mouse with a disrupted Atm gene [28].

References