| Non-Scientific Abstract Understanding the molecular basis of cancer
development has been a fundamental problem in biology for the past fifty years.Work in cancer research
established a genetic basis for cancer development through mutations in key cell-cycle regulatory
genes or in genes that help maintain genomic stability. Genomic stability and integrity help maintain
functional copies of cell cycle regulatory genes, and thus reduced genomic stability can lead to
accumulation of mutations and ultimately cancer. It has been suggested that DNA methylation, a process
in which DNA is chemically modified through addition of methyl groups, plays a role in chromosome
stability and therefore tumor formation.Abnormal DNA methylation patterns have been observed in tumor
cells, often correlating with early stages of cancer. The following study investigates the role of
reduced methylation levels ‹ hypomethylation ‹ in chromosome stability in a mouse embryonic fibroblast
system.Results from this investigation suggest that hypomethylation causes chromosomal instability
leading to loss of function in cell cycle regulatory genes.
Abstract
DNA hypomethylation is an epigenetic phenomenon that has been suggested to play a role in
carcinogenesis.One of the proposed mechanisms through which this may occur is chromosomal instability
caused by genome-wide hypomethylation. Destabilized genomes may be more susceptible to mutations and
loss of heterozygosity (LOH) in regions containing tumor suppressor genes or other regulatory genes.
The following study investigates the effects of hypomethylation on genomic instability by measuring
LOH rates in mouse embryonic fibroblasts with hypomethylated genomes established through a hypomorphic
allele.We report here that hypomethylated fibroblasts show an increased LOH rate compared to normally
methylated fibroblasts. The major chromosomal event observed in hypomethylated fibroblasts was whole
chromosome loss. Both these findings suggest a critical role for hypomethylation in promoting genomic
instability and tumor development. | 