In search of drug treatment for genetic defects in the DNA damage response: The example of ataxia-telangiectasia

Yosef Shiloh*, Yair Andegeko, Ilan Tsarfaty

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish
Pages (from-to)295-305
Number of pages11
JournalSeminars in Cancer Biology
Issue number4
StatePublished - Aug 2004


FundersFunder number
David and Inez Myers Foundation
Israel Ministry of Science
National Cancer Institute
National Institute of Neurological Disorders and Stroke
Dr. Ralph and Marian Falk Medical Research Trust
Israel Science Foundation
Medical Research Foundation


    • A-T
    • A-T-like disease
    • A-TLD
    • ATM
    • ATM- and Rad3-related (protein)
    • ATR
    • CFP
    • DNA-PK
    • DNA-dependent protein kinase
    • DSB
    • FRET
    • ataxia-telangiectasia
    • ataxia-telangiectasia, mutated
    • cyan fluorescent protein
    • double strand break


    Dive into the research topics of 'In search of drug treatment for genetic defects in the DNA damage response: The example of ataxia-telangiectasia'. Together they form a unique fingerprint.

    Cite this