This project stems from our long-standing goal to treat ATM deficiency, whether this be in cancer patients or in those suffering from ataxia-telangiectasia (A-T), a rare neurodegenerative disorder of children for which no treatment exists. Recently, we have obtained exciting evidence that certain antibiotic aminoglycosides, such as gentamicin and geneticin, induce the readthrough of premature termination codon (PTC) mutations in the ATM gene. The resulting ATM protein is functional, in that it corrects the radiosensitivity of A-T cells, phosphorylates ATM targets, and partially restores the S phase checkpoint, as demonstrated by measurement of radioresistant DNA synthesis. There is reason to believe that during the development of antibiotic aminoglycosides, over the past 40 years, many compounds were developed and screened for antimicrobial activity but not for PTC readthrough ability. High throughput screening will be developed, using assays based on protein truncation testing, to screen for new readthrough drugs. Promising compounds will then be further evaluated in secondary cell-based assays for ATM function, using mutations and cell lines that correspond to patient mutations. Tertiary testing will investigate the readthrough efficiency of various stop codons and the effect of the +4 nucleotide of each termination codon. Aminoglycoside-induced readthrough will be tested in combination with ATM promoter inducers in an effort to further boost intracellular ATM levels. A mouse model carrying a PTC mutation in the ATM gene will be generated for animal testing of selected drugs. Biomarkers will be developed for following in vivo responses to aminoglycoside treatment. These efforts are encouraged by the rationale that ATM heterozygotes live essentially normal lives with less than 50 percent of normal ATM protein levels. Furthermore, a subset of A-T patients with <15 percent of normal ATM protein tends to manifest less severe disease. These studies may impact upon other genetic disorders as well, and upon cancer patients with low levels of ATM protein. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-C (02))
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Tagle, Danilo A
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Martin, Nathan T; Nakamura, Kotoka; Davies, Robert et al. (2013) ATM-dependent MiR-335 targets CtIP and modulates the DNA damage response. PLoS Genet 9:e1003505
Du, Liutao; Jung, Michael E; Damoiseaux, Robert et al. (2013) A new series of small molecular weight compounds induce read through of all three types of nonsense mutations in the ATM gene. Mol Ther 21:1653-60
Lee, Peiyee; Martin, Nathan T; Nakamura, Kotoka et al. (2013) SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs. Nat Commun 4:1824
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Nakamura, Kotoka; Du, Liutao; Tunuguntla, Rashmi et al. (2012) Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia. Hum Mutat 33:198-208
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Martin, Nathan T; Nahas, Shareef A; Tunuguntla, Rashmi et al. (2011) Assessing 'radiosensitivity' with kinetic profiles of ?-H2AX, 53BP1 and BRCA1 foci. Radiother Oncol 101:35-8

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