Three decades ago, the theory of “immortal DNA” was put forward,1 suggesting that stem cells could conserve the original copy of their genome, division after division. Because genetic mutations are susceptible to arise during DNA replication, when cells divide, retaining the template strand rather than a copy would enable stem cells to better protect themselves against mutational errors that lead, in some cases, to cancers.
“Many efforts have been made to prove this theory, but little direct evidence has emerged in the past thirty years, leaving the scientific community quite skeptical,” says Shahragim Tajbakhsh, CNRS researcher at the Pasteur Institute.2
However, recent findings suggest that immortal DNA is present in some tissues. In 2002, for example, it was found in stem cells of the small intestine in mice. In vitro experiments have suggested it also exists in the central nervous system. Now a study led by Tajbakhsh's team, recently published in Nature Cell Biology,3 demonstrates that immortal DNA is also present in skeletal muscle stem cells in mice.
Using videomicroscopy and genetic labeling techniques, the researchers identified a subpopulation of stem cells and followed the fate of their DNA during asymmetric division. Asymmetric division is a mechanism of self-renewal that stem cells use to replace themselves while generating a more specialized sibling cell.
In this process, after DNA is duplicated, it is distributed among the two daughter cells. At this point, according to the immortal DNA theory, only cells destined to differentiate will inherit the “copied” DNA strand, which might contain more errors. The stem cells will conserve the original DNA strands, which remain “immortal” after repeated cell divisions.
“This model is also controversial because it defies basic rules of cellular biology, which presume that genetic material is distributed randomly to daughter cells,” says Tajbakhsh.
Challenging the basic rules, the team's in vitro and in vivo experiments show that muscle stem cells can retain their template DNA strands. Thus, asymmetrical and non-random cosegregation of DNA also occurs in skeletal muscle.
“How the cellular machinery distinguishes old DNA from new is still a mystery,” says Tajbakhsh. “For me, it is one of the most fascinating questions regarding DNA since the double helix was first described.”
1. Cairns, “Mutation selection and the natural history of cancer,” Nature. 255: 197-200. 1975.
2. Cellules souches et developpement (CNRS / Institut Pasteur joint lab).
3. Shinin et al., “Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells,” Nature Cell Biology. 8 (7): 677-87. 2006.
Institut Pasteur, Paris.