More than just strand breaks: the recognition of structural DNA discontinuities by DNA-dependent protein kinase catalytic subunit.
The DNA-dependent protein kinase (DNA-PK) is a trimeric factor originally identified as an enzyme that becomes activated upon incubation with DNA. Genetic defects in either the catalytic subunit (DNA-PK(CS)) or the two Ku components of DNA-PK result in immunodeficiency, radiosensitivity, and premature aging. This combined phenotype is generally attributed to the requirement for DNA-PK in the repair of DNA double strand breaks during various biological processes. However, recent studies revealed that DNA-PK(CS), a member of the growing family of phosphatidylinositol 3-kinases, participates in signal transduction cascades related to apoptotic cell death, telomere maintenance and other pathways of genome surveillance. These manifold functions of DNA-PK(CS) have been associated with an increasing number of protein interaction partners and phosphorylation targets. Here we review the DNA binding properties of DNA-PK(CS) and highlight its ability to interact with an astounding diversity of nucleic acid substrates. This survey indicates that the large catalytic subunit of DNA-PK functions as a sensor of not only broken DNA molecules, but of a wider spectrum of aberrant, unusual, or specialized structures that interrupt the standard double helical conformation of DNA.
Dip
Ramiro
R
Institute of Veterinary Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.
Naegeli
Hanspeter
H
D020134:Catalytic Domain / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair; D045566:DNA, Cruciform / Q000737:chemistry / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000737:chemistry* / Q000378:metabolism*; D004789:Enzyme Activation; D006706:Homeostasis; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D010766:Phosphorylation; D011995:Recombination, Genetic; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D016615:Telomere
D045566:DNA, Cruciform; D004247:DNA; D051747:DNA-Activated Protein Kinase