Sci. Aging Knowl. Environ., 11 December 2002
Famous chromosome-protecting protein helps maintain master copy of DNA in stem cells
Key Words: asymmetric cell kinetics immortal DNA strands semiconservative replication tumor suppressor protein
Copying a copy of a copy can produce an unreadable document. Similarly, a lifetime of cell divisions can blur an organism's DNA sequence. To preserve an uncorrupted version, splitting stem cells direct the original chromosomes into one of their cellular offspring and pack freshly made chromosomes into the other. New research hints that the protein p53, which protects nonstem cells from turning cancerous, also helps stem cells safeguard a master copy of the genome. The work might help clarify how stem cells produce progeny and yet remain undefiled.
Stem cells supply a variety of fresh cells to adult organisms. To restock tissue, a stem cell divides in two: One daughter cell specializes, and the other remains a stem cell. But the DNA replication machinery makes mistakes; left uncorrected, each cellular generation would carry more mutations than the preceding one. p53 limits but does not prevent this accruing genetic chaos by blocking growth of cells with error-laden DNA. For decades, researchers have suspected that in order to maintain a supply of stem cells that is free from mutations, the stem cells throw the newly manufactured DNA into the cell destined to become tissue. Investigators have recently started gathering evidence to support this idea. In June, scientists reported that mouse stem cells replenishing the lining of the intestine can hang onto a clean copy of their DNA. Now, Merok and colleagues uncover a molecular mechanism by which stem cells accomplish that feat.
In previous research, Merok and colleagues serendipitously created a stem cell-like culture. They started with mouse cells that propagated uncontrollably because they lacked p53, which would normally curb growth. Resupplying p53 generated cells that produce one daughter that reproduces normally and another that stops duplicating, as specialized cells eventually do.
Because the behavior of cells with active p53 mimicked the asymmetric division of adult stem cells, the culture offered the researchers an opportunity to test whether p53 helped maintain unsullied DNA strands in stem cells--an unusual opportunity, given the difficulty of isolating the real thing. First, the researchers engineered the p53 gene so that they could turn it on and off. They turned off p53 and allowed the dividing cells to incorporate a molecule called BrdU into newly made DNA. Then they switched on p53. If the stem cell-like cells distributed fresh DNA equally between their two progeny, the researchers reasoned, BrdU would show up in both daughter cells. However, the DNA label appeared only in the daughter cells that retained reproduction capability, indicating that the stem cell-like cells retained the original version of the DNA. Additional research is required to verify that stem cells in intact animals also use p53 in this manner.
"The p53 result is exciting," says molecular biologist Lawrence Donehower of Baylor College of Medicine in Houston, Texas. "It provides another dimension" to the protein. Not only does p53 protect regular cells from becoming cancerous, but the protein "keeps stem cells pristine" by immortalizing their DNA. The work provides a starting point from which researchers can probe the unorthodox reproductive methods of stem cells.
J. R. Merok, J. A. Lansita, J. R. Tunstead, J. L. Sherley, Cosegregation of chromosomes containing immortal DNA strands in cells that cycle with asymmetric stem cell kinetics, Cancer Res. 62, 6791-6795 (2002). [Abstract] [Full Text]
December 11, 2002 Citation: M. Beckman, Molecular Immortality. Science's SAGE KE (11 December 2002), http://sageke.sciencemag.org/cgi/content/full/sageke;2002/49/nw164
Science of Aging Knowledge Environment. ISSN 1539-6150