Targeting ATM pathway for therapeutic intervention in cancer

Hilal S. Khalil, Hemanth Tummala, Stoyan Chakarov, Nikolai Zhelev, David P. Lane

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Abstract

The Ataxia Telangiectasia Mutated gene encodes the ATM protein, a key element in the DNA damage response (DDR) signalling pathway responsible for maintaining genomic integrity within the cell. The ATM protein belongs to a family of large protein kinases containing the phosphatidylinositol-3 catalytic domain, including ATM, ATR and PI3K. ATM provides the crucial link between DNA damage, cell cycle progression and cell death by first sensing double stranded DNA breaks and subsequently phosphorylating and activating other downstream proteins functioning in DNA damage repair, cell cycle arrest and apoptotic pathways,. Mammalian cells are constantly challenged by genotoxic agents from a variety of sources and therefore require a robust sensing and repair mechanism to maintain DNA integrity or activate alternative cell fate pathways. This review covers the role of ATM in DDR signalling and describes the interaction of the ATM kinase with other proteins in order to fulfil its various functions. Special emphasis is given to how the growing knowledge of the DDR can help identify drug targets for cancer therapy, thus providing a rationale for exploiting the ATM pathway in anticancer drug development. Moreover, we discuss how a network modelling approach can be used to identify and characterise ATM inhibitors and predict their therapeutic potential.
Original languageEnglish
Number of pages13
JournalBioDiscovery
Volume1
Issue number3
DOIs
Publication statusPublished - 29 Jul 2012

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DNA Damage
Ataxia Telangiectasia Mutated Proteins
Neoplasms
Therapeutics
Ataxia Telangiectasia
Double-Stranded DNA Breaks
Phosphatidylinositols
Cell Cycle Checkpoints
Phosphatidylinositol 3-Kinases
DNA Repair
Pharmaceutical Preparations
Protein Kinases
Catalytic Domain
Cell Cycle
Proteins
Cell Death
Phosphotransferases
DNA
Genes

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Khalil, H. S., Tummala, H., Chakarov, S., Zhelev, N., & Lane, D. P. (2012). Targeting ATM pathway for therapeutic intervention in cancer. BioDiscovery, 1(3). https://doi.org/10.7750/BioDiscovery.2012.1.3
Khalil, Hilal S. ; Tummala, Hemanth ; Chakarov, Stoyan ; Zhelev, Nikolai ; Lane, David P. / Targeting ATM pathway for therapeutic intervention in cancer. In: BioDiscovery. 2012 ; Vol. 1, No. 3.
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Khalil, HS, Tummala, H, Chakarov, S, Zhelev, N & Lane, DP 2012, 'Targeting ATM pathway for therapeutic intervention in cancer', BioDiscovery, vol. 1, no. 3. https://doi.org/10.7750/BioDiscovery.2012.1.3

Targeting ATM pathway for therapeutic intervention in cancer. / Khalil, Hilal S.; Tummala, Hemanth; Chakarov, Stoyan; Zhelev, Nikolai; Lane, David P.

In: BioDiscovery, Vol. 1, No. 3, 29.07.2012.

Research output: Contribution to journalArticle

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