| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
The Institute for Cancer Research, Fox Chase Center for Cancer and Medical Sciences, Philadelphia, Pennsylvania 19111
In this essay we have considered possible relationships between errors in DNA replication and malignant progression. Theoretical and experimental studies designed to determine the energy of interaction between different nucleotides have been reviewed. The difference of the energy of interaction between complementary and noncomplementary base pairs (1 to 3 kcal) is not sufficient to account for the exactness of DNA replication that is observed in vivo or in vitro. Thus, DNA polymerases must play a role in base selection. This point has been established by the detection of polymerases that copy polynucleotide templates with few errors and the detection of others that make many errors. Different mechanisms for base selection by polymerases have been considered. Our findings that both extracts of human leukemic lymphocytes and a purified DNA polymerase from avian myeloblastosis virus have exceptionally high error rates have been considered in relationship to oncogenesis. A hypothesis is presented that relates mistakes in DNA replication, as promoted by error-prone DNA polymerases, to tumor progression. We have also considered a more general concept encompassing early cellular changes that lead to oncogenesis. The justification for this essay is that both of these hypotheses are open to immediate experimental analysis.
1 This investigation was supported by grants from the NIH (CA-11524, CA-12818) and the National Science Foundation (GB-36812), by grants to this Institute from NIH (CA-06927, RR-05539), and by an appropriation from the Commonwealth of Pennsylvania.
2 Also a member of the Department of Pathology, School of Medicine, University of Pennsylvania, Philadelphia, Pa. 19104.
3 Postdoctoral fellow of the Leukemia Society of America.
4 Predoctoral associate, Graduate Group on Molecular Biology, University of Pennsylvania, Philadelphia, Pa. 19104.
Received 3/13/74. Accepted 5/30/74.
This article has been cited by other articles:
|
|
 |
|
  E. J. Fox, J. J. Salk, and L. A. Loeb Cancer Genome Sequencing--An Interim Analysis Cancer Res., June 15, 2009; 69(12): 4948 - 4950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Loeb and C. C. Harris Advances in Chemical Carcinogenesis: A Historical Review and Prospective Cancer Res., September 1, 2008; 68(17): 6863 - 6872. [Full Text] [PDF]
|
|
|
|
|
|
L. A. Loeb, J. H. Bielas, R. A. Beckman, and I. W. Bodmer Cancers Exhibit a Mutator Phenotype: Clinical Implications Cancer Res., May 15, 2008; 68(10): 3551 - 3557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dalal, A. Chikova, J. Jaeger, and J. B. Sweasy The Leu22Pro tumor-associated variant of DNA polymerase beta is dRP lyase deficient Nucleic Acids Res., February 2, 2008; 36(2): 411 - 422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. L Komarova, A. V Sadovsky, and F. Y.M Wan Selective pressures for and against genetic instability in cancer: a time-dependent problem J R Soc Interface, January 6, 2008; 5(18): 105 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Lang, S. Dalal, A. Chikova, D. DiMaio, and J. B. Sweasy The E295K DNA Polymerase Beta Gastric Cancer-Associated Variant Interferes with Base Excision Repair and Induces Cellular Transformation Mol. Cell. Biol., August 1, 2007; 27(15): 5587 - 5596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Chan, S. Houlbrook, Q.-M. Zhang, M. Harrison, I. D. Hickson, and G. L. Dianov Overexpression of DNA polymerase {beta} results in an increased rate of frameshift mutations during base excision repair Mutagenesis, May 1, 2007; 22(3): 183 - 188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Bielas, K. R. Loeb, B. P. Rubin, L. D. True, and L. A. Loeb From the Cover: Human cancers express a mutator phenotype PNAS, November 28, 2006; 103(48): 18238 - 18242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Klein Random mutations, selected mutations: A PIN opens the door to new genetic landscapes PNAS, November 28, 2006; 103(48): 18033 - 18034. [Full Text] [PDF]
|
|
|
|
|
|
J. R. Hart, O. Glebov, R. J. Ernst, I. R. Kirsch, and J. K. Barton DNA mismatch-specific targeting and hypersensitivity of mismatch-repair-deficient cells to bulky rhodium(III) intercalators PNAS, October 17, 2006; 103(42): 15359 - 15363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Beckman and L. A. Loeb Efficiency of carcinogenesis with and without a mutator mutation PNAS, September 19, 2006; 103(38): 14140 - 14145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Emily and O. Francois Conditional Coalescent Trees With Two Mutation Rates and Their Application to Genomic Instability Genetics, March 1, 2006; 172(3): 1809 - 1820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Beckman and L. A. Loeb Negative Clonal Selection in Tumor Evolution Genetics, December 1, 2005; 171(4): 2123 - 2131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. L. Komarova and D. Wodarz Drug resistance in cancer: Principles of emergence and prevention PNAS, July 5, 2005; 102(27): 9714 - 9719. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Michor Chromosomal instability and human cancer Phil Trans R Soc B, March 29, 2005; 360(1455): 631 - 635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. B. Smilenov, H. B. Lieberman, S. A. Mitchell, R. A. Baker, K. M. Hopkins, and E. J. Hall Combined Haploinsufficiency for ATM and RAD9 as a Factor in Cell Transformation, Apoptosis, and DNA Lesion Repair Dynamics Cancer Res., February 1, 2005; 65(3): 933 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Nowak, F. Michor, N. L. Komarova, and Y. Iwasa Evolutionary dynamics of tumor suppressor gene inactivation PNAS, July 20, 2004; 101(29): 10635 - 10638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. P. Bignold Carcinogen-induced impairment of enzymes for replicative fidelity of DNA and the initiation of tumours Carcinogenesis, March 1, 2004; 25(3): 299 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Iwasa, F. Michor, and M. A. Nowak Stochastic Tunnels in Evolutionary Dynamics Genetics, March 1, 2004; 166(3): 1571 - 1579. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dalal, J. L. Kosa, and J. B. Sweasy The D246V Mutant of DNA Polymerase {beta} Misincorporates Nucleotides: EVIDENCE FOR A ROLE FOR THE FLEXIBLE LOOP IN DNA POSITIONING WITHIN THE ACTIVE SITE J. Biol. Chem., January 2, 2004; 279(1): 577 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Lee, D. K. Chang, A. Goel, C. R. Boland, W. Bugbee, D. L. Boyle, and G. S. Firestein Microsatellite Instability and Suppressed DNA Repair Enzyme Expression in Rheumatoid Arthritis J. Immunol., February 15, 2003; 170(4): 2214 - 2220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Loeb, K. R. Loeb, and J. P. Anderson Multiple mutations and cancer PNAS, February 4, 2003; 100(3): 776 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Nowak, N. L. Komarova, A. Sengupta, P. V. Jallepalli, I.-M. Shih, B. Vogelstein, and C. Lengauer The role of chromosomal instability in tumor initiation PNAS, December 10, 2002; 99(25): 16226 - 16231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Liu, W. Liu, J. L. Jakubczak, G. L. Erexson, K. R. Tindall, R. Chan, W. J. Muller, S. Adhya, S. Garges, and G. Merlino Genetic instability favoring transversions associated with ErbB2-induced mammary tumorigenesis PNAS, March 19, 2002; 99(6): 3770 - 3775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Chicurel Dangerous Liaisons Sci. Aging Knowl. Environ., October 3, 2001; 2001(1): oa3 - 3. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Loeb A Mutator Phenotype in Cancer Cancer Res., April 1, 2001; 61(8): 3230 - 3239. [Abstract] [Full Text]
|
|
|
|
|
|
C.-Y. Li, J. B. Little, K. Hu, W. Zhang, L. Zhang, M. W. Dewhirst, and Q. Huang Persistent Genetic Instability in Cancer Cells Induced by Non-DNA-damaging Stress Exposures Cancer Res., January 1, 2001; 61(2): 428 - 432. [Abstract] [Full Text]
|
|
|
|
|
|
K. R. Loeb and L. A. Loeb Significance of multiple mutations in cancer Carcinogenesis, March 1, 2000; 21(3): 379 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Gryfe, H. Kim, E. T.K. Hsieh, M. D. Aronson, E. J. Holowaty, S. B. Bull, M. Redston, and S. Gallinger Tumor Microsatellite Instability and Clinical Outcome in Young Patients with Colorectal Cancer N. Engl. J. Med., January 13, 2000; 342(2): 69 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Clairmont, L. Narayanan, K.-W. Sun, P. M. Glazer, and J. B. Sweasy The Tyr-265-to-Cys mutator mutant of DNA polymerase beta induces a mutator phenotype in mouse LN12 cells PNAS, August 17, 1999; 96(17): 9580 - 9585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Philpott and G. C. Buehring Defective DNA Repair in Cells With Human T-Cell Leukemia/Bovine Leukemia Viruses: Role of tax Gene J Natl Cancer Inst, June 2, 1999; 91(11): 933 - 942. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Loeb and L. A. Loeb Genetic Instability and the Mutator Phenotype : Studies in Ulcerative Colitis Am. J. Pathol., June 1, 1999; 154(6): 1621 - 1626. [Full Text] [PDF]
|
|
|
|
|
|
A. L. Jackson, R. Chen, and L. A. Loeb Induction of microsatellite instability by oxidative DNA damage PNAS, October 13, 1998; 95(21): 12468 - 12473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Jackson and L. A. Loeb The Mutation Rate and Cancer Genetics, April 1, 1998; 148(4): 1483 - 1490. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. S. Strauss Hypermutability in Carcinogenesis Genetics, April 1, 1998; 148(4): 1619 - 1626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Modrich Strand-specific Mismatch Repair in Mammalian Cells J. Biol. Chem., October 3, 1997; 272(40): 24727 - 24730. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Perucho, M.A. Peinado, Y. Ionov, S. Casares, S. Malkhosyan, and E. Stanbridge Defects in Replication Fidelity of Simple Repeated Sequences Reveal a New Mutator Mechanism for Oncogenesis Cold Spring Harb Symp Quant Biol, January 1, 1994; 59(0): 339 - 348. [Abstract] [PDF]
|
|
|
|
|
|
E. Harlow An Introduction to the Puzzle Cold Spring Harb Symp Quant Biol, January 1, 1994; 59(0): 709 - 723. [Abstract] [PDF]
|
|
|
|
|
|
M. Theile, M. Strauss, L. Luebbe, S. Scherneck, H. Krause, and E. Geissler SV40-induced Somatic Mutations: Possible Relevance to Viral Transformation Cold Spring Harb Symp Quant Biol, January 1, 1980; 44(0): 377 - 382. [Abstract] [PDF]
|
|
|
|
|
|
L. A. Loeb, L. A. Weymouth, T. A. Kunkel, K. P. Gopinathan, R. A. Beckman, and D. K. Dube On the Fidelity of DNA Replication Cold Spring Harb Symp Quant Biol, January 1, 1979; 43(0): 921 - 927. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Sirover and L. Loeb Infidelity of DNA synthesis in vitro: screening for potential metal mutagens or carcinogens Science, December 24, 1976; 194(4272): 1434 - 1436. [Abstract] [PDF]
|
|
|
|
|
|
R. B. Chadwick, G.-L. Jiang, G. A. Bennington, B. Yuan, C. K. Johnson, M. W. Stevens, T. H. Niemann, P. Peltomaki, S. Huang, and A. de la Chapelle Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis PNAS, March 14, 2000; 97(6): 2662 - 2667. [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 |
