Immortal DNA strand hypothesis

The immortal DNA strand hypothesis was proposed in 1975 by John Cairns as a mechanism for adult stem cells to minimize mutations in their genomes. This hypothesis proposes that instead of segregating their DNA during mitosis in a random manner, adult stem cells retain a distinct template set of DNA strands (parental strands) in each division. By retaining the same set of template DNA strands, adult stem cells would pass mutations arising from errors in DNA replication on to non-stem cell daughters. Passing on these replication errors would allow adult stems cells to reduce their rate of accumulation of mutations that could lead to cancer. Although evidence for this mechanism exists, whether it is a mechanism acting in adult stem cells in vivo is still controversial.

Evidence

Evidence for the immortal strand hypothesis has been found in various systems. One of the earliest studies by Lark et al. demonstrated co-segregation of DNA in the cells of plant root tips . Plant root tips labeled with tritiated thymidine tended to segregate their labeled DNA to the same daughter cell. Though not all the labeled DNA segregated to the same daughter, the amount of thymidine-labeled DNA seen in the daughter with less label corresponded to the amount that would have arisen from sister-chromatid exchange . Later studies by Potten et al. (2002) , using pulse/chase experiments with tritiated thymidine, found long-term label-retaining cells in the small intestinal crypts of neonatal mice to demonstrate the existence of long-term label-retaining cells. These researchers hypothesized that long-term incorporation of tritiated thymidine occurred because neonatal mice have undeveloped small intestines, and that pulsing tritiated thymidine soon after the birth of the mice allowed the DNA of adult stem cells to be labeled during their formation. These long-term cells were demonstrated to be actively cycling, as demonstrated by incorporation and release of BrdU . Merok et al. engineered mammalian cells with an inducible p53 gene that controls asymmetric divisions. Bromodeoxyuridine pulse/chase experiments with these cells demonstrated that chromosomes segregated non-randomly only when the cells were induced to divide asymmetrically like adult stem cells. These asymmetrically dividing cells provide a simple in vitro model for demonstration and investigation of immortal strand mechanisms.

These experiments supporting the immortal strand hypothesis, however, are not conclusive. While the Lark experiments demonstrated co-segregation, the co-segregation may have been an artifact of radiation from the tritium. Although Potten identified the cycling, label-retaining cells as adult stem cells, these cells are difficult to identify unequivocally as adult stem cells. While the engineered cells provide an elegant model for co-segregation of chromosomes, studies with these cells were done in vitro with engineered cells. Some features may not be present in vivo or may be absent in vitro.

Experimental evidence against the immortal strand hypothesis is sparse. In one study, researchers incorporated tritiated thymidine into dividing murine epidermal basal cells They followed the release of tritiated thymidine after various chase periods, but the pattern of release was not consistent with the immortal strand hypothesis. Although they found label-retaining cells, they were not within the putative stem cell compartment. With increasing lengths of time for the chase periods, these label-retaining cells were located farther from the putative stem cell compartment, suggesting that the label-retaining cells had moved. However, finding conclusive evidence against the immortal strand hypothesis has proven difficult.