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Abstract
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.