Potential role of DNA polymerase beta in gene therapy against cancer: a case for colorectal cancer.
Genetic instability characterized by the accumulation of mutations of tumor suppressor genes and oncogenes appears to be associated with carcinogenesis in colorectal and other cancers. Mutations of DNA polymerase beta (pol beta) and related chromosomal alterations appear to be consistent with the causal role of a "mutator phenotype' in carcinogenesis. However, homozygous knockout pol beta mutations appear to interfere with embryogenesis. Increased pol beta activity (i.e. relative to pol alpha activity) has been associated with cell cycle arrest. The related aphidicolin-resistant DNA replication has been observed primarily in differentiating cells, including the mammalian blastocyst, adrenal cortex, thyroid, anterior pituitary, and the mechanism of endoreduplication (amitotic over-replication of DNA) can be traced to lower eukaryotes. This increased activity in relation to terminal commitment is inconsistent with a simple "DNA repair' view of pol beta. It is therefore proposed that pol beta may play a more fundamental role in cellular differentiation through involvement in a putative subgenomic DNA replication-based model of terminal gene expression. Thus genetic instability, loss of differentiation, and carcinogenesis may result from aberration(s) or "derailment' of such replication-based mechanism of terminal gene expression. It is suggested to examine the relationship of DNA pol beta to genomic instability and carcinogenesis using genetic analyses and antisense technology with possible applications for gene therapy against colorectal cancer.
Shadan
F F
FF
Department of Molecular Biology and Biochemistry, University of California, Irvine 92717, USA.
Villarreal
L P
LP
D000818:Animals; D001755:Blastocyst / Q000502:physiology; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000235:genetics / Q000628:therapy*; D004256:DNA Polymerase I / Q000096:biosynthesis / Q000235:genetics*; D004261:DNA Replication; D005314:Embryonic and Fetal Development; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D006801:Humans; D008322:Mammals; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D009857:Oncogenes
D004256:DNA Polymerase I