Cancers of the microsatellite mutator phenotype (MMP) show exaggerated genomic instability at simple repeat sequences. More than 50 percent (21 out of 41) of human MMP+ colon adenocarcinomas examined were found to have frameshift mutations in a tract of eight deoxyguanosines [(G)8] within BAX, a gene that promotes apoptosis. These mutations were absent in MMP- tumors and were significantly less frequent in (G)8 repeats from other genes. Frameshift mutations were present in both BAX alleles in some MMP+ colon tumor cell lines and in primary tumors. These results suggest that inactivating BAX mutations are selected for during the progression of colorectal MMP+ tumors and that the wild-type BAX gene plays a suppressor role in a p53-independent pathway for colorectal carcinogenesis.

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We have established a method for the detection of DNA damage and its repair in human telomeres, the natural ends of chromosomes which are necessary for replication and critical for chromosomal stability. We find that ultraviolet light-induced pyrimidine dimers in telomeric DNA are repaired less efficiently than endogenous genes but more efficiently than inactive, noncoding regions. We have also measured telomeric length, telomeric DNA damage, and its repair in relation to the progression of aging. Telomeres are shorter in fibroblasts from an old donor compared to fibroblasts from a young donor, shortest in cells from a patient with the progeroid disorder Werner syndrome, and relatively long in fibroblasts from a patient with Alzheimer disease. Telomeric DNA repair efficiency is lower in cells from an old donor than in cells from a young donor, normal in Alzheimer cells, and slightly lower in Werner cells. It is possible that this decline in telomeric repair with aging is of functional significance to an age-related decline in genomic stability.

Changes in conformation, length, and mobility of individual DNA molecules during agarose gel electrophoresis were measured using video micrographs obtained by epifluorescence microscopy. Globular, V-shaped, and linear conformations of DNA are found. The mobility, upon transformation from the globular to the V-shaped conformation, decreases, suggesting a collision with a gel fiber. The duration of interaction between DNA and gel fiber is proportional to the length of DNA. Hypothetically, this proportionality underlies the size separation of DNA by agarose gel electrophoresis. DNA release from the gel fiber appears to involve the movement of the arms of the V-shaped molecule around the gel fiber. Concomitant with this movement is a length reduction the degree of which is constant for DNA of various lengths in a particular buffer milieu. The luminant densitometric profiles of DNA molecules in the V conformation show maxima at the ends and apex of the V. The unequal distribution of nucleotides along the DNA chain appears to provide the driving force for the molecular movement around the gel fiber.