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Assessing DNA topoisomerase binding in the myeloid-lympoid leukemia gene translocation breakpoint region.(COMMUNICATIONS--UNDERGRADUATE)(Report)
Background/Objective: The mixed-lineage leukemia gene, (MLL), breaks and fuses to one of >50 different translocation partner genes in several subtypes of de novo human acute leukemia. All breaks in MLL occur within the same 8 kilobase (kb) region, (bcr) and create in-frame fusion mRNAs and fusion proteins with the translocation partner gene. MLL fusions are also observed in chemotherapy-related, secondary leukemias. These MLL fusions often follow treatment with drugs for cancer which interfere with the endonuclease DNA topoisomerase II (topo II) activity and implicate topo II in the translocation mechanism, in vivo.
To date, all evidence supporting topo II as a DNA cleaving agent in MLL translocations is indirect and includes the clinical cases discussed above as well as in vitro cleavage studies of topo II inhibitors. However, no one has shown direct binding of DNA topo II in the MLL bcr. Since it is possible that topo II could act at sites outside the MLL bcr and alter the accessibility of the bcr to other DNA damaging agents, it is important to show whether the MLL bcr directly binds topo II. The objective of this study, then, has been to assay the affinity of topo II for regions of the MLL bcr.
Methods: We are using chromatin immunoprecipitation (ChIP) to assay binding of topo II specifically in the MLL bcr. Human leukemia cell lines with normal MLL genes (intact MLL bcr) are treated with DNA topo II inhibitors and then with formaldehyde to cross-link and stabilize all protein-DNA interactions. (DNA topo II inhibitors covalently link topo II to DNA at sites of binding.) Cells are lysed and DNA is sheared into ...
- Analysis of protein binding in the MLL translocation breakpoint...
- Magazine article from: Proceedings of the North Dakota Academy of Science Super, Heidi J. Anderson, Alysa L. Aldrich, Aileen April 1, 2007 700+ words
...analysis has been done to characterize the MLL bcr to elucidate the mechanism of MLL translocation...begun analyzing protein binding in the MLL bcr using electrophoretic mobility shift assay...provide insight into the regions of the MLL bcr which are necessary for recombination...
- Analysis of chromatin structure in the myeloid-lymphoid leukemia gene...
- Magazine article from: Proceedings of the North Dakota Academy of Science Horrell, Jeremy C. Aldrich, Aileen M. Anderson, Alysa L. Super, Heidi J. April 1, 2009 700+ words
...protein binding characteristics in the MLL bcr. Proteins were noted to bind at the extreme boundaries of the MLL bcr, but not in an internal region noted...may bind at the 5' and 3' ends of the MLL bcr. Binding occurred with nuclear proteins...
- Analysis of protein binding in the myeloid-lymphoid leukemia gene translocation...
- Magazine article from: Proceedings of the North Dakota Academy of Science Aldrich, Aileen M. Anderson, Alysa L. Super, Heidi J. April 1, 2008 700+ words
...bcr). A number of studies indicate the MLL bcr is susceptible to DNA cleaving agents...sequence or chromatin structure in the MLL bcr. Therefore, the objective of this study...protein binding characteristics of the MLL bcr. We have used an electrophoretic mobility...
- DNA cleavage in vitro by DNA topoisomerase II in the AF4 Gene translocation...
- Magazine article from: Proceedings of the North Dakota Academy of Science Olander, Ashley L. Lepp, Cheryl A. Super, Heidi J. April 1, 2007 700+ words
...inhibitor, etoposide. Plasmid DNA from the cloned AF4 bcr, the MLL bcr, and a control plasmid (pRYG) was incubated at 37 degrees...single strong topo II cleavage site. Etoposide cleaved both the MLL bcr plasmid and the AF4 bcr plasmid at a single site as both plasmids...
- Reports summarize lymphoma study results from T. Numbenjapon and...
- Newspaper article from: Blood Weekly October 1, 2009 700+ words
...inhibiting type I DNA topoisomerase (DNA topo I). It has not been used clinically...pharmacokinetics, inhibitions of tumor DNA topo I catalytic activity, and antilymphoma...and significantly inhibit higher tumor DNA topo I catalytic activities. Furthermore...
- Research from National Heart, Lung, & Blood Institute provides new data about...
- Newspaper article from: Medical Devices & Surgical Technology Week July 5, 2009 700+ words
...discrimination arises primarily from dramatic differences in the processivity of relaxing positive and negative supercoiled DNA: Topo IV is highly processive on positively supercoiled DNA, whereas it is perfectly distributive on negatively supercoiled DNA...
- Findings from J.G. Turner et al in myeloma reported.
- Newspaper article from: Blood Weekly October 22, 2009 700+ words
...assay. Band depletion assays of CRM1 inhibitor-exposed myeloma cells showed increased topo II alpha covalently bound to DNA. Topo II alpha knockdown by a topo II alpha-specific siRNA abrogated the CRM1-topo II therapy synergistic effect. These results...
- Studies from University of Delaware reveal new findings on DNA research.(Report)
- Newspaper article from: Medical Devices & Surgical Technology Week November 16, 2008 700+ words
...alpha/primase (pol/prim) to synthesize larger amounts of primers consisting of short RNA and about 30 nucleotides of DNA. Topo I binding also Stimulates the production of large molecular weight DNA by pol/prim. Mutant T antigens that fail to bind...