Tumor suppressor genes, which encode proteins that normally inhibit aberrant cell proliferation, are frequently mutated in human cancer. In most cases, cells with one normal copy of a particular tumor suppressor gene (heterozygosity) will not give rise to a tumor. When the normal copy is lost, however, a cell is predisposed to abnormal proliferation and, if enough mutations accumulate, to tumor formation. This 'loss of heterozygosity,' or LOH, is a rate-limiting step in tumorigenesis, but its causes are not fully understood.
One way in which LOH can occur is through mitotic recombination, in which homologous chromosomes exchange DNA when they are lined up during the process of cell division. A group led by Jay Tischfield (of Rutgers University) has now shown that the level of mitotic recombination in mice is affected by the degree of relatedness between the two sets of chromosomes, one set being inherited from each parent (Nature Genetics, Vol. 28, No. 2, 01 June 2001). Tischfield and colleagues studied mice that carry only one copy of the gene encoding the enzyme adenine phosphoribosyltransferase (Aprt). Mitotic recombination events in which Aprt is lost, resulting in LOH, can be identified because those cells completely lacking Aprt survive when cultured in the presence of diaminopurine (DAP), whereas cells containing Aprt cannot.
As recombination depends on a high level of DNA sequence identity, the authors hypothesized that mitotic recombination would be suppressed in the hybrid offspring of two distantly related strains of mice whose chromosomes have diverged in sequence. Indeed, fibroblasts isolated from such mice are found to have a dramatically lower frequency of mitotic recombination events when compared to fibroblasts taken from the offspring of two closely related strains. Interestingly, however, mitotic recombination is not suppressed in T-lymphocytes, suggesting that there are tissue-specific mechanisms involved.
In an accompanying News & Views article, Harry Vrieling (of Leiden University Medical Center, The Netherlands) expands on the relevance of these findings for human disease. For example, it may be that small genetic differences between individuals are sufficient to suppress mitotic recombination in certain tissues, thereby reducing the risk of cancer. And, in a provocative conclusion to their paper, the authors suggest that the degree of DNA sequence similarity between parents may be a contributing factor in determining the susceptibility of their offspring to diseases, like cancer, that are associated with mitotic recombination and LOH.
Dr. Jay Tischfield
Rutgers, the State University of New Jersey
Picataway, New Jersey, USA.
Telephone: +1 (732) 445 1027
Fax: +1 (732) 445 1148
Dr. Harry Vrieling
Telephone: +31 715-276-148
Fax: +31 715-221-615
(C) Nature Genetics press release.
Message posted by: Trevor M. D'Souza
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