Sci. Aging Knowl. Environ., 15 January 2003
Vol. 2003, Issue 2, p. nw9
[DOI: 10.1126/sageke.2003.2.nw9]

NOTEWORTHY ARTICLES

Overturned Ends

Ribosomes trump telomeres in premature-aging disease

Mary Beckman

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/2/nw9

Key Words: pseudouridylation • pseudouridine • telomerase

Like a new SUV whose tires blow out, a mutant protein spurs a premature-aging disease by causing an unanticipated problem. The new results suggest that a defect in protein production plays a stronger role in causing this syndrome than previously thought. Questions remain, however, about how accurately the mouse affliction portrays the human disease.

The inherited disease dyskeratosis congenita (DC) confers agelike conditions on its victims: It wipes out their bone marrow, predisposes them to a variety of cancers, and gives them splotchy skin and ratty fingernails. Previous research showed that defects in a protein called dyskerin can cause the illness. Dyskerin has two functions: It chemically modifies ribosomal RNA, which is required to produce the cell's proteinmaking factories--ribosomes--and it sticks to an RNA component of telomerase, the enzyme that builds telomeres, the structures that cap chromosomes (see "More Than a Sum of Our Cells"). Researchers originally thought that the human dyskerin mutations impeded ribosomal RNA modification. Results with cultured cells from DC patients, however, showed that ribosomal RNA carried the usual chemical tweaks. Instead, the cells harbored reduced amounts of telomerase RNA. In the absence of dyskerin, scientists speculated, defenseless telomeres would shorten with every cell division, eventually becoming too small to protect chromosome ends.

Molecular biologist Davide Ruggero of the Memorial Sloan-Kettering Cancer Center in New York City and colleagues sought a line of DC mice. A rare mutation ruins the activation portions of the dyskerin gene and presumably reduces the amount of dyskerin produced by cells. To simulate the effects of this mutation, the group engineered mice to generate one-fourth to one-half the normal amount of dyskerin. Mice have longer telomeres than humans do, and unprotected telomeres would not be expected to adversely affect mutant mice until the third or fourth generation. The researchers examined rodents in the first two generations to assess whether a DC-like condition arose before that.

The animals had malfunctioning bone marrow, bad skin, and lung and mammary tumors, indicative of DC. In addition, cells from the mutant mice contained 10% to 40% fewer chemical modifications in ribosomal RNA--an alteration expected to interfere with ribosome assembly. Telomere length didn't change until the fourth generation. "Our working hypothesis is that protein synthesis is defective," Ruggero says. The problems in DC occur in tissues that constantly regenerate, and impeding protein production could disrupt this tissue replenishment.

"This paper seems to have swung the pendulum back to RNA; therefore it's of considerable interest," says geneticist Philip Mason of Imperial College in London. But biochemist Kathleen Collins of the University of California, Berkeley, says that scientists have looked for problems with ribosome function in human DC and haven't found any, raising questions about the mice as a relevant model. Not all of the genes that cause DC have been found, however, and the new work suggests that scientists should look at genes that affect ribosome assembly as well as those that influence telomeres, Collins and Mason agree. A thorough dyskerin checkup might explain why patient health breaks down prematurely.

--Mary Beckman

D. Ruggero, S. Grisendi, F. Piazza, E. Rego, F. Mari, P. H. Rao, C. Cordon-Cardo, P. P. Pandolfi, Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science 299, 259-262 (2003). [Abstract] [Full Text]


January 15, 2003 Citation: M. Beckman, Overturned Ends. Science's SAGE KE (15 January 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/2/nw9








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