TY - JOUR
T1 - In search of drug treatment for genetic defects in the DNA damage response
T2 - The example of ataxia-telangiectasia
AU - Shiloh, Yosef
AU - Andegeko, Yair
AU - Tsarfaty, Ilan
N1 - Funding Information:
We wish to thank our colleagues at Tel Aviv University for helpful comments on the manuscript and Michal Semo for fine art work. Work in the laboratory of Y.S. is supported by the A-T Medical Research Foundation, The A-T Children’s Project, The A-T Medical Research Trust, The National Institute of Neurological Disorders and Stroke, The Israel Science Foundation, the Israel Ministry of Science, and the David and Inez Myers Foundation. Work in the laboratory of I.T. is supported by The Israel Science Foundation and the p50 National Cancer Institute grant.
PY - 2004/8
Y1 - 2004/8
N2 - Most genetic disorders are severe diseases that cannot be treated. In the majority of them, enzyme and gene therapy can be significantly curtailed by technical difficulties and the nature of the physiological defects and affected tissues. A rational search for drug treatment for such diseases must be based on understanding the corresponding molecular defects. For example, in a disease stemming from a defective signaling pathway, a drug that can activate redundant pathways could be useful. Screening for such a drug would then depend on the availability of a laboratory assay that faithfully reflects the molecular defect in the corresponding disease, and a technology for applying the assay in a high throughput setup. Deficiencies in various components of the DNA damage response lead to genomic instability syndromes characterized by tissue degeneration, sensitivity to DNA damaging agents, and cancer predisposition. A typical example is ataxia-telangiectasia (A-T), caused by deficiency of the nuclear protein kinase ATM, which activates the cellular response to double strand breaks in the DNA. ATM phosphorylates a multitude of substrates, each of which in turn modulates a branch of the damage response network. A certain redundancy among ATM and related proteins gives hope that activation of ATM-redundant activities might form a basis for drug treatment of A-T. This article describes a high throughput strategy for drug screening for A-T that is based on the above principles. A similar strategy can potentially be applied to drug screening for other genetic disorders.
AB - Most genetic disorders are severe diseases that cannot be treated. In the majority of them, enzyme and gene therapy can be significantly curtailed by technical difficulties and the nature of the physiological defects and affected tissues. A rational search for drug treatment for such diseases must be based on understanding the corresponding molecular defects. For example, in a disease stemming from a defective signaling pathway, a drug that can activate redundant pathways could be useful. Screening for such a drug would then depend on the availability of a laboratory assay that faithfully reflects the molecular defect in the corresponding disease, and a technology for applying the assay in a high throughput setup. Deficiencies in various components of the DNA damage response lead to genomic instability syndromes characterized by tissue degeneration, sensitivity to DNA damaging agents, and cancer predisposition. A typical example is ataxia-telangiectasia (A-T), caused by deficiency of the nuclear protein kinase ATM, which activates the cellular response to double strand breaks in the DNA. ATM phosphorylates a multitude of substrates, each of which in turn modulates a branch of the damage response network. A certain redundancy among ATM and related proteins gives hope that activation of ATM-redundant activities might form a basis for drug treatment of A-T. This article describes a high throughput strategy for drug screening for A-T that is based on the above principles. A similar strategy can potentially be applied to drug screening for other genetic disorders.
KW - A-T
KW - A-T-like disease
KW - A-TLD
KW - ATM
KW - ATM- and Rad3-related (protein)
KW - ATR
KW - CFP
KW - DNA-PK
KW - DNA-dependent protein kinase
KW - DSB
KW - FRET
KW - ataxia-telangiectasia
KW - ataxia-telangiectasia, mutated
KW - cyan fluorescent protein
KW - double strand break
UR - http://www.scopus.com/inward/record.url?scp=3042513631&partnerID=8YFLogxK
U2 - 10.1016/j.semcancer.2004.04.009
DO - 10.1016/j.semcancer.2004.04.009
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AN - SCOPUS:3042513631
SN - 1044-579X
VL - 14
SP - 295
EP - 305
JO - Seminars in Cancer Biology
JF - Seminars in Cancer Biology
IS - 4
ER -