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 divide their DNA asymmetrically, and 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 that soon terminally differentiate (end mitotic divisions and become a functional cell). Passing on these replication errors would allow adult stem cells to reduce their rate of accumulation of mutations that could lead to serious genetic disorders such as cancer.

Although evidence for this mechanism exists, whether it is a mechanism acting in adult stem cells in vivo is still controversial.

Two main assays are used to detect immortal DNA strand segregation: label-retention and label-release pulse/chase assays.

In the label-retention assay, the goal is to mark 'immortal' or parental DNA strands with a DNA label such as tritiated thymidine or bromodeoxyuridine (BrdU). These types of DNA labels will incorporate into the newly synthesized DNA of dividing cells during S phase. A pulse of DNA label is given to adult stem cells under conditions where they have not yet delineated an immortal DNA strand. During these conditions, the adult stem cells are either dividing symmetrically (thus with each division a new 'immortal' strand is determined and in at least one of the stem cells the immortal DNA strand will be marked with DNA label), or the adult stem cells have not yet been determined (thus their precursors are dividing symmetrically, and once they differentiate into adult stem cells and choose an 'immortal' strand, the 'immortal strand' will already have been marked). Experimentally, adult stem cells are undergoing symmetric divisions during growth and after wound healing, and are not yet determined at neonatal stages. Once the immortal DNA strand is labelled and the adult stem cell has begun or resumed asymmetric divisions, the DNA label is chased out. In symmetric divisions (most mitotic cells), DNA is segregating randomly and the DNA label will be diluted out to levels below detection after five divisions. If, however, cells are using an immortal DNA strand mechanism, then all the labeled DNA will continue to co-segregate with the adult stem cell, and after five (or more) divisions will still be detected within the adult stem cell. These cells are sometimes called label-retaining cells (LRCs).

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