DNA repair mechanisms relocate in response to stress

March 27, 2009

Like doctors making house calls, some DNA repair enzymes can relocate to the part of the cell that needs their help, a collaborative team of scientists at Emory University School of Medicine has found.

The signal that prompts relocation is oxidative stress, an imbalance of cellular metabolism connected with several human diseases.

The study integrated the expertise of three Emory groups and resulted in a new level of understanding of the cell's response to genetic damage. The finding could lead to new targets for anti-cancer drugs that interfere with DNA repair, says Paul Doetsch, PhD, professor of biochemistry, radiation oncology, and hematology and oncology at Emory University School of Medicine.

The results were published in the February 1 issue of Molecular and Cellular Biology. The journal's editors chose an image of yeast cells with fluorescent DNA repair enzymes for the cover.

"DNA damage and oxidative stress are very closely related," Doetsch says. "For example, the way radiation inflicts most of its damage on DNA is through oxidative stress. The more we know about how cells respond to oxidative stress, the more chances there could be to influence those responses for diagnostic or therapeutic purposes."

The DNA inside cells is continually under assault by heat, radiation and oxygen. Cells have an extensive set of repair enzymes that comb through DNA, continually excising and re-copying damaged segments. To complicate matters, mitochondria (cells' miniature power plants) have their own DNA.

Working with Doetsch, Emory graduate students Lyra Griffiths and Dan Swartzlander, and biochemists Anita Corbett and Keith Wilkinson, genetically modified strains of yeast so that two different DNA repair enzymes would be fluorescent. They were able to follow the enzymes around the cell when yeast was exposed to hydrogen peroxide, causing oxidative stress, or to other chemicals causing DNA damage.

One DNA repair enzyme they studied, Ntg1, moves to the nucleus or the mitochondria depending on where DNA damage is concentrated, the authors found. In contrast, a related enzyme, Ntg2, stays in the nucleus under all conditions.

Cells appear to direct Ntg1's relocation by briefly attaching a small protein called SUMO to what needs to be moved around, the authors found. SUMO is found in fungi, plants and animals and is already being investigated by several research groups as a possible target for anti-cancer drugs.

Emory University

---

---

	DNA Repair And Mutagenesis by Errol C. Friedberg (Author), Graham C. Walker (Author), Wolfram Siede (Author), Richard D. Wood (Author), Roger A. Schultz (Author), Tom Ellenberger (Author) Featuring more than 10,000 references and a text lavishly complemented by over 700 illustrations, "DNA Repair and Mutagenesis, Second Edition" is a timely update to the original edition published in 1995. This work: features three new authors, including an expert in the field of structural biology, ensures a comprehensive review of the most current research in diverse subject areas; presents timely updates to the only comprehensive textbook in the field of DNA repair; offers contributions by recognized experts in the field; provides a strong historical context for comprehensive review of material; features a 12-page, full-color insert and over 700 illustrations, including protein structures; and, covers all aspects of biological responses to DNA damage.
	DNA Repair in Cancer Therapy: Molecular Targets and Clinical Applications by Mark R. Kelley PhD (Editor) Cancer therapeutics include an ever-increasing array of tools at the disposal of clinicians in their treatment of this disease. However, cancer is a tough opponent in this battle, and current treatments, which typically include radiotherapy, chemotherapy and surgery, are not often enough to rid the patient of his or her cancer. Cancer cells can become resistant to the treatments directed at them, and overcoming this drug resistance is an important research focus. Additionally, increasing discussion and research is centering on targeted and individualized therapy. While a number of approaches have undergone intensive and close scrutiny as potential approaches to treat and kill cancer (signaling pathways, multidrug resistance, cell cycle checkpoints, anti-angiogenesis, etc.), other...
	DNA Damage Repair: Repair Mechanisms and Aging (DNA: Properties and Modifications, Functions and Interactions, Recombination and Applications) by Allison E. Thomas (Editor)
	DNA Repair in Cancer Therapy (Cancer Drug Discovery and Development) by Lawrence C. Panasci (Editor), Moulay A. Alaoui-Jamali (Editor) A comprehensive review of the recent developments in DNA repair that have potential for translational and clinical applications. The authors explain in detail the various mechanisms by which cancer cells can circumvent anticancer therapy and limits its usefulness in patients. They also review the clinical impact of such novel inhibitors of DNA repair mechanisms as methylguanine-DNA-methyltransferase. Also examined are inhibitors of other DNA repair enzymes such as PARP and DNA-PK, now under development and close to clinical trials. The book captures-for both cancer researchers and practicing oncologists dealing with hallmark "relapse" or "drug resistance" phenomena on a daily basis-the many exciting new uses of DNA repair inhibitors, either alone or in combination with anticancer...
	DNA Damage and Repair: Volume III: Advances from Phage to Humans (Contemporary Cancer Research) by Jac A. Nickoloff (Editor), Merl F. Hoekstra (Editor) Jac A. Nickoloff and Merl F. Hoekstra update and expand their two earlier acclaimed volumes (Vol. I: DNA Repair in Prokaryotes and Lower Eukaryotes and Vol. II: DNA Repair in Higher Eurkaryotes) with cutting-edge reviews by leading authorities of primary experimental findings about DNA repair processes in cancer biology. The reviews cover a wide range of topics from viruses and prokaryotes to higher eukaryotes, and include several new topics, among them the role of recombination in replication of damaged DNA, X-ray crystallographic analysis of DNA repair protein structures, DNA repair proteins and teleomere function, and the roles of BRCA1 and BRCA2 in DNA repair. Authoritative and up-to-date, DNA Damage and Repair, Vol. III: Advances from Phage to Humans surveys the rapidly moving...
	DNA Damage and Repair: Volume II: DNA Repair in Higher Eukaryotes (Contemporary Cancer Research) by Jac A. Nickoloff (Editor), Merl F. Hoekstra (Editor) Cutting edge reviews by leading researchers illuminate key aspects of DNA repair in mammalian systems and its relationship to human genetic disease and cancer. Major topics include UV and X-Ray repair, repair of chemical damage, recombinational repair, mismatch repair, transcription-repair coupling, and the role of DNA repair in disease prevention. Extensive up-to-date references and rigorous peer-review of each chapter make this volume definitive and bring it to the active frontiers of research.
	Perturbation of DNA repair gene expression due to interspecies hybridization [An article from: Comparative Biochemistry and Physiology, Part C] by S.J. Heater (Author), J.D. Rains (Author), M.C. Wells (Author), P.A Guerrero (Author) This digital document is a journal article from Comparative Biochemistry and Physiology, Part C, published by Elsevier in 2007. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: The effect of interspecies hybridization on gene regulation was examined using real-time polymerase chain reaction (RT-PCR) to measure the expression of five base-excision repair genes in brain, eye, gill, liver, and tailfin tissues from Xiphophorus parental species and F"1 hybrids. Relative mRNA levels of uracil N-glycosylase (Ung), Apurinic/apyrimidinic endonuclease (Ape1), polymerase-@b (Polb), flap endonuclease (Fen1), and DNA ligase (Lig1) were measured in three parental...
	The rate of extrachromosomal homologous recombination within a novel reporter plasmid is elevated in cells lacking functional ATM protein [An article from: DNA Repair] by G.A. Drexler (Author), S. Wilde (Author), W. Beisker (Author), J. Ellwart (Author), Ec (Author) This digital document is a journal article from DNA Repair, published by Elsevier in 2004. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: Homologous recombination between identical stretches of DNA depends on the coordinated action of many tightly regulated proteins. Cellular defects in homologous recombination are strongly associated with increased genomic instability and tumorigenesis. In cells of the cancer-prone syndrome ataxia telangiectasia (A-T), increased intrachromosomal recombination has been demonstrated, while extrachromosomal recombination has been discussed controversially. We constructed a novel, episomally replicating pGrec recombination...
	DNA Repair: New Research by Sakura Kimura (Editor), Sora Shimizo (Editor)
	Correcting the Blueprint of Life: An Historical Account of the Discovery of DNA Repair Mechanisms (History) by Errol C. Friedberg (Author) A brief history of the discovery of the more important mechanisms by which cells respond to DNA damage. The study, which introduces the study of DNA mutagenesis and repair, is aimed at advanced undergraduates or graduate students, as well as researchers in a variety of fields.