Molecular Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Bridging the Lab and the Clinic in Cancer Medicine
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Allen, C.
Right arrow Articles by Nickoloff, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Allen, C.
Right arrow Articles by Nickoloff, J. A.
Molecular Cancer Research 1:913-920 (2003)
© 2003 American Association for Cancer Research

DNA Damage and Cellular Stress Responses

Interactive Competition Between Homologous Recombination and Non-Homologous End Joining1

Chris Allen1, James Halbrook2 and Jac A. Nickoloff1

1 Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, and
2 ICOS Corporation, Bothell, WA

Requests for reprints: Jac A. Nickoloff, Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131. Phone: (505) 272-6960; Fax: (505) 272-6029. E-mail: jnickoloff{at}salud.unm.edu

DNA-dependent protein kinase (DNA-PK), composed of Ku70, Ku80, and the catalytic subunit (DNA-PKcs), is involved in double-strand break (DSB) repair by non-homologous end joining (NHEJ). DNA-PKcs defects confer ionizing radiation sensitivity and increase homologous recombination (HR). Increased HR is consistent with passive shunting of DSBs from NHEJ to HR. We therefore predicted that inhibiting the DNA-PKcs kinase would increase HR. A novel DNA-PKcs inhibitor (1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone; designated IC86621) increased ionizing radiation sensitivity but surprisingly decreased spontaneous and DSB-induced HR. Wortmannin also inhibits DNA-PKcs and reduces DSB-induced HR. IC86621 did not affect HR product outcome, indicating that it affects HR initiation. Thus, HR is increased in the absence of DNA-PKcs, but decreased when DNA-PKcs is catalytically inactive, suggesting interactive competition between HR and NHEJ. The effects of IC86621 and wortmannin were proportional to the level of DNA-PKcs, consistent with inhibited DNA-PKcs acting in a dominant negative manner. We propose that inhibition of DNA-PKcs blocks its autophosphorylation, prevents dissociation of DNA-PKcs from DNA ends, and thereby blocks both HR and NHEJ. By blocking the two major DSB repair pathways, DNA-PKcs inhibitors should radiosensitize at all cell-cycle stages and are therefore excellent candidates for augmenting cancer radiotherapy.

Key Words: DNA double-strand breaks • DNA-dependent protein kinase • spontaneous homologous recombination • ionizing radiation




This article has been cited by other articles:


Home page
 Nucleic Acids ResHome page
W. Y. Mansour, S. Schumacher, R. Rosskopf, T. Rhein, F. Schmidt-Petersen, F. Gatzemeier, F. Haag, K. Borgmann, H. Willers, and J. Dahm-Daphi
Hierarchy of nonhomologous end-joining, single-strand annealing and gene conversion at site-directed DNA double-strand breaks
Nucleic Acids Res., July 1, 2008; 36(12): 4088 - 4098.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. Sallmyr, J. Fan, K. Datta, K.-T. Kim, D. Grosu, P. Shapiro, D. Small, and F. Rassool
Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML
Blood, March 15, 2008; 111(6): 3173 - 3182.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
L. Amrein, M. Loignon, A.-C. Goulet, M. Dunn, B. Jean-Claude, R. Aloyz, and L. Panasci
Chlorambucil Cytotoxicity in Malignant B Lymphocytes Is Synergistically Increased by 2-(Morpholin-4-yl)-benzo[h]chomen-4-one (NU7026)-Mediated Inhibition of DNA Double-Strand Break Repair via Inhibition of DNA-Dependent Protein Kinase
J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 848 - 855.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. E. White, D. Negorev, H. Peng, A. V. Ivanov, G. G. Maul, and F. J. Rauscher III
KAP1, a Novel Substrate for PIKK Family Members, Colocalizes with Numerous Damage Response Factors at DNA Lesions
Cancer Res., December 15, 2006; 66(24): 11594 - 11599.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
A. Vasileva, R. M. Linden, and R. Jessberger
Homologous recombination is required for AAV-mediated gene targeting
Nucleic Acids Res., July 5, 2006; 34(11): 3345 - 3360.
[Abstract] [Full Text] [PDF]

Home page
 GeneticsHome page
I. Clejan, J. Boerckel, and S. Ahmed
Developmental Modulation of Nonhomologous End Joining in Caenorhabditis elegans
Genetics, July 1, 2006; 173(3): 1301 - 1317.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Zhao, H. D. Thomas, M. A. Batey, I. G. Cowell, C. J. Richardson, R. J. Griffin, A. H. Calvert, D. R. Newell, G. C.M. Smith, and N. J. Curtin
Preclinical Evaluation of a Potent Novel DNA-Dependent Protein Kinase Inhibitor NU7441.
Cancer Res., May 15, 2006; 66(10): 5354 - 5362.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. Damaraju, D. Murray, J. Dufour, D. Carandang, S. Myrehaug, G. Fallone, C. Field, R. Greiner, J. Hanson, C. E. Cass, et al.
Association of DNA Repair and Steroid Metabolism Gene Polymorphisms with Clinical Late Toxicity in Patients Treated with Conformal Radiotherapy for Prostate Cancer
Clin. Cancer Res., April 15, 2006; 12(8): 2545 - 2554.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
C. M. Sturgeon, Z. A. Knight, K. M. Shokat, and M. Roberge
Effect of combined DNA repair inhibition and G2 checkpoint inhibition on cell cycle progression after DNA damage.
Mol. Cancer Ther., April 1, 2006; 5(4): 885 - 892.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
H. Grabsch, M. Dattani, L. Barker, N. Maughan, K. Maude, O. Hansen, H. E. Gabbert, P. Quirke, and W. Mueller
Expression of DNA Double-Strand Break Repair Proteins ATM and BRCA1 Predicts Survival in Colorectal Cancer
Clin. Cancer Res., March 1, 2006; 12(5): 1494 - 1500.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
M. Jovanovic and W. S. Dynan
Terminal DNA structure and ATP influence binding parameters of the DNA-dependent protein kinase at an early step prior to DNA synapsis
Nucleic Acids Res., February 18, 2006; 34(4): 1112 - 1120.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H.-C. Wang, W.-C. Chou, S.-Y. Shieh, and C.-Y. Shen
Ataxia Telangiectasia Mutated and Checkpoint Kinase 2 Regulate BRCA1 to Promote the Fidelity of DNA End-Joining
Cancer Res., February 1, 2006; 66(3): 1391 - 1400.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
X. Cui, Y. Yu, S. Gupta, Y.-M. Cho, S. P. Lees-Miller, and K. Meek
Autophosphorylation of DNA-Dependent Protein Kinase Regulates DNA End Processing and May Also Alter Double-Strand Break Repair Pathway Choice
Mol. Cell. Biol., December 15, 2005; 25(24): 10842 - 10852.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
C. Di Primio, A. Galli, T. Cervelli, M. Zoppe, and G. Rainaldi
Potentiation of gene targeting in human cells by expression of Saccharomyces cerevisiae Rad52
Nucleic Acids Res., August 16, 2005; 33(14): 4639 - 4648.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
H. J. Boeckman, K. S. Trego, and J. J. Turchi
Cisplatin Sensitizes Cancer Cells to Ionizing Radiation via Inhibition of Nonhomologous End Joining
Mol. Cancer Res., May 1, 2005; 3(5): 277 - 285.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
E. Convery, E. K. Shin, Q. Ding, W. Wang, P. Douglas, L. S. Davis, J. A. Nickoloff, S. P. Lees-Miller, and K. Meek
Inhibition of homologous recombination by variants of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs)
PNAS, February 1, 2005; 102(5): 1345 - 1350.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
R. Fan, T. S. Kumaravel, F. Jalali, P. Marrano, J. A. Squire, and R. G. Bristow
Defective DNA Strand Break Repair after DNA Damage in Prostate Cancer Cells: Implications for Genetic Instability and Prostate Cancer Progression
Cancer Res., December 1, 2004; 64(23): 8526 - 8533.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. O. Nowicki, R. Falinski, M. Koptyra, A. Slupianek, T. Stoklosa, E. Gloc, M. Nieborowska-Skorska, J. Blasiak, and T. Skorski
BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks
Blood, December 1, 2004; 104(12): 3746 - 3753.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
L. Ferrara and E. B. Kmiec
Camptothecin enhances the frequency of oligonucleotide-directed gene repair in mammalian cells by inducing DNA damage and activating homologous recombination
Nucleic Acids Res., October 5, 2004; 32(17): 5239 - 5248.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. V. R. Reddy, Q. Ding, S. P. Lees-Miller, K. Meek, and D. A. Ramsden
Non-homologous End Joining Requires That the DNA-PK Complex Undergo an Autophosphorylation-dependent Rearrangement at DNA Ends
J. Biol. Chem., September 17, 2004; 279(38): 39408 - 39413.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
W. D. Block, Y. Yu, D. Merkle, J. L. Gifford, Q. Ding, K. Meek, and S. P. Lees-Miller
Autophosphorylation-dependent remodeling of the DNA-dependent protein kinase catalytic subunit regulates ligation of DNA ends
Nucleic Acids Res., August 16, 2004; 32(14): 4351 - 4357.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
S. M. Bailey, M. A. Brenneman, and E. H. Goodwin
Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells
Nucleic Acids Res., July 16, 2004; 32(12): 3743 - 3751.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Geng, J. Tan, E. Himmelfarb, A. Schueneman, K. Niermann, A. Fu, K. Cuneo, E. A. Kesicki, J. Treiberg, J. S. Hayflick, et al.
A Specific Antagonist of the p110{delta} Catalytic Component of Phosphatidylinositol 3'-Kinase, IC486068, Enhances Radiation-Induced Tumor Vascular Destruction
Cancer Res., July 15, 2004; 64(14): 4893 - 4899.
[Abstract] [Full Text] [PDF]

Home page
 Sci Aging Knowl EnvironHome page
R. J. Monnat Jr. and Y. Saintigny
Werner Syndrome Protein--Unwinding Function to Explain Disease
Sci. Aging Knowl. Environ., March 31, 2004; 2004(13): re3 - re3.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2003 by the American Association for Cancer Research.