title: Cross talk of tyrosine kinases with the DNA damage signaling pathways.
abstract: Tyrosine kinases respond to extracellular and intracellular cues by activating specific cellular signaling cascades to regulate cell cycle, growth, proliferation, differentiation and survival. Likewise, DNA damage response proteins (DDR) activated by DNA lesions or chromatin alterations recruit the DNA repair and cell cycle checkpoint machinery to restore genome integrity and cellular homeostasis. Several new examples have been uncovered in recent studies which reveal novel epigenetic and non-epigenetic mechanisms by which tyrosine kinases interact with DDR proteins to dictate cell fate, i.e. survival or apoptosis, following DNA damage. These studies reveal the ability of tyrosine kinases to directly regulate the activity of DNA repair and cell cycle check point proteins by tyrosine phosphorylation. In addition, tyrosine kinases epigenetically regulate DNA damage signaling pathways by modifying the core histones as well as chromatin modifiers at critical tyrosine residues. Thus, deregulated tyrosine kinase driven epigenomic alterations have profound implications in cancer, aging and genetic disorders. Consequently, targeting oncogenic tyrosine kinase induced epigenetic alterations has gained significant traction in overcoming cancer cell resistance to various therapies. This review discusses mechanisms by which tyrosine kinases interact with DDR pathways to regulate processes critical for maintaining genome integrity as well as clinical strategies for targeted cancer therapies.
authors.affiliation: Tumor Biology Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA Department of Oncological Sciences, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA kiran.mahajan@moffitt.org.
authors.forename: Kiran
authors.initials: K
authors.lastname: Mahajan
authors.affiliation: Drug Discovery Department, Moffitt Cancer Center, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA Department of Oncological Sciences, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA nupam.mahajan@moffitt.org.
authors.forename: Nupam P
authors.initials: NP
authors.lastname: Mahajan
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D006657:Histones; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases