POTENTIAL ROLE OF DNA-POLYMERASE-BETA IN GENE-THERAPY AGAINST CANCER - A CASE FOR COLORECTAL-CANCER

Genetic instablility characterized by the accumulation of mutations of tumor suppressor genes and oncogenes appears to be associated with ca rcinogenesis in colorectal and other cancers. Mutations of DNA polymer ase beta (pol beta) and related chromosomal alterations appear to be c onsistent with the causal role of a 'mutator phenotype' in carcinogene sis. However, homozygous knockout pol beta mutations appear to interfe re with embryogenesis. Increased pol beta activity (i.e. relative to p ol alpha activity) has been associated with cell cycle arrest. The rel ated aphidicolin-resistant DNA replication has been observed primarily in differentiating cells, including the mammalian blastocyst, adrenal cortex, thyroid, anterior pituitary, and the mechanism of endoredupli cation (amitotic over-replication of DNA) can be traced to lower eukar yotes. This increased activity in relation to terminal commitment is i nconsistent with a simple 'DNA repair' view of pol beta. It is therefo re proposed that pol beta may play a more fundamental role in cellular differentiation through involvement in a putative subgenomic DNA repl ication-based model of terminal gene expression. Thus genetic instabil ity, loss of differentiation, and carcinogenesis may result from aberr ation(s) or 'derailment' of such replication-based mechanism of termin al gene expression. It is suggested to examine the relationship of DNA pol beta to genomic instability and carcinogenesis using genetic anal yses and antisense technology with possible applications for gene ther apy against colorectal cancer.