sullivjo Posted May 28, 2017 Posted May 28, 2017 (edited) The Ku complex is essential for DNA repair following double strand breaks following exposure to X-Rays. Potential inhibitors of this Ku complex could either block its interaction with the DNA backbone by binding as an anionic phosphate analogue or block formation of the required Ku70/Ku80 heterodimer for DNA repair. These inhibitors can be selectively targeted to cancer cells by conjugation to a macromolecule such as polyethylene glycol which should enter tumour cells via the EPR effect or monoclonal antibodies which bind biomarkers. Could selective inhibition of this Ku complex within malignant tumours with subsequent exposure to X-Rays be an effective method of shrinking tumours or at least be a potential topic of research? Reference; Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair, John R. Walker1,2, Richard A. Corpina & Jonathan Goldberg, Nature 412, 607-614 (9 August 2001) Edited May 28, 2017 by sullivjo
Function Posted May 28, 2017 Posted May 28, 2017 (edited) You give us a reference from 2001 (for those who are still aghast by hearing from another point of view: 16 years ago). In a domain such as oncology, that's way outdated. Oncological research is evolving so fast that you'd at least need a reference from the last 5 years. On the same subject. If not, forget about it. It's unthinkable that no other person with time, money, and the task to do so, has already thought about it and researched it. Old articles (yes, 2001 is old) may provide you some general concepts and insights in the fundamentals of oncology. But when it comes especially to genetics, and whole protein families, you can't rely on something that old for researching something new. Edited May 28, 2017 by Function
jimmydasaint Posted May 28, 2017 Posted May 28, 2017 You give us a reference from 2001 (for those who are still aghast by hearing from another point of view: 16 years ago). In a domain such as oncology, that's way outdated. Oncological research is evolving so fast that you'd at least need a reference from the last 5 years. On the same subject. If not, forget about it. It's unthinkable that no other person with time, money, and the task to do so, has already thought about it and researched it. Old articles (yes, 2001 is old) may provide you some general concepts and insights in the fundamentals of oncology. But when it comes especially to genetics, and whole protein families, you can't rely on something that old for researching something new. Thank you Function. I support what you say. Oncology references need to be recent - I must confess that I did not see the reference properly. However, I did search it up and I have copied the abstract here: The Ku heterodimer (Ku70 and Ku80 subunits) contributes to genomic integrity through its ability to bind DNA double-strand breaks and facilitate repair by the non-homologous end-joining pathway. The crystal structure of the human Ku heterodimer was determined both alone and bound to a 55-nucleotide DNA element at 2.7 and 2.5 Å resolution, respectively. Ku70 and Ku80 share a common topology and form a dyad-symmetrical molecule with a preformed ring that encircles duplex DNA. The binding site can cradle two full turns of DNA while encircling only the central 3–4 base pairs (bp). Ku makes no contacts with DNA bases and few with the sugar-phosphate backbone, but it fits sterically to major and minor groove contours so as to position the DNA helix in a defined path through the protein ring. These features seem well designed to structurally support broken DNA ends and to bring the DNA helix into phase across the junction during end processing and ligation. http://www.nature.com/nature/journal/v412/n6847/full/412607a0.html The abstract refers to a protein, Ku made of two polypeptide chains bonded together that stabilises damaged DNA by encircling it, IIRC. The question must be asked from the writer of the OP, which cancers involve damage to both strands of DNA? How widespread are these? What is the possibility of using Ku as cancer treatment.
sullivjo Posted May 28, 2017 Author Posted May 28, 2017 X-Rays cause the damage to both strands of DNA, if the Ku protein function is inhibitted, the DNA will be irreparably damaged which should trigger apoptosis.
jimmydasaint Posted May 28, 2017 Posted May 28, 2017 You did not answer the question my friend. I asked which cancers involve damage to both strands of DNA? As prolonged X-rays in Western society would come from exposure to X-ray generators in hospitals why is this relevant to cancer therapy generally?
sauerkrautpie Posted May 29, 2017 Posted May 29, 2017 (edited) X-Rays cause the damage to both strands of DNA, if the Ku protein function is inhibitted, the DNA will be irreparably damaged which should trigger apoptosis. Well, we call it cancer because it can't trigger apoptosis and its DNA is damaged. And it is unrepairable. Second thing, there is a thing already named "Chemotherapy" for prevent uncontrolled proliferation of cancer cells. Edited May 29, 2017 by sauerkrautpie
Function Posted May 29, 2017 Posted May 29, 2017 (edited) Well, we call it cancer because it can't trigger apoptosis and its DNA is damaged. And it is unrepairable. Second thing, there is a thing already named "Chemotherapy" for prevent uncontrolled proliferation of cancer cells. In fact, lots of chemotherapeutic agents aim to damage DNA and block DNA repair mechanisms to force even malign cells into apoptosis. (Radiation therapy works in a comparable way) Edited May 30, 2017 by Function 2
jimmydasaint Posted May 30, 2017 Posted May 30, 2017 In fact, lots of chemotherapeutic agents aim to damage DNA and block DNA repair mechanisms to force even malign cells into apoptosis. (Radiation therapy works in a comparable way) Once again, thank you for stepping in and clarifying matters Function. I actually had a post-doctoral position to examine relationship of viral DNA and some cancers, but never saw the chemotherapy or radiotherapy side of the research - another danger of over-specialisation in research - everyone is seeing an elephant from a different point of view.
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