Translating cancer

When we consider factors that contribute to tumorigenesis, we typically think of defects such as oncogene activation, apoptosis inhibition and angiogenesis induction. A study published by Davide Ruggero et al. in the 10 January issue of Science reveals that deregulated ribosome function might soon be added to this list.

Ruggero et al. became involved in investigating ribosome regulation through their studies of dyskeratosis congenita (DC) — a rare X-linked recessive disease that is caused by point mutations in the DKC1 gene. DC is characterized by premature ageing, mucosal leukoplakia, interstital fibrosis of the lung and increased susceptibility to cancer. DKC1 encodes dyskerin — a pseudouridine synthase that mediates post-transcriptional modification of ribosomal RNA, through conversion of uridine to pseudouridine. Dyskerin also physically associates with the RNA component of telomerase, hTR, to regulate telomere length. So which one of these functions, or both, could be involved in cancer susceptibility?

To answer this question, the authors generated Dkc1-mutant mice (Dkc1^m), which express decreased levels of the gene product. The first and second generations of Dkc1^m mice did not display any overt developmental defects at birth, but by 6 months of age they developed features of bone-marrow failure — one characteristic of human DC. Some 50% of Dkc1^m mice also developed cancer, with tumours arising from a variety of histological origins — the most common being the lung and mammary gland. These phenotypes are similar to those of people with DC, indicating that these mice are a faithful model of the human disease.

But how do defects in Dkc1 lead to cancer? Human DC cell lines have reduced telomerase activity and shorter telomeres, so this defect was the most likely candidate to underlie the observed cancer susceptibility. But quantitative fluorescence in situ hybridization analysis showed that there were no detectable changes in telomere length in cells of first- or second-generation Dkc1^m mice. In fact, shortened telomeres could not be detected in these mice until the fourth generation.

So, telomere shortening was not required for cancer development in first- and second-generation Dkc1^m mice. In taking another look at the cells of these early-generation mice, the authors detected a 10–40% reduction in pseudouridine modification and processing of rRNA. These cells were also hypersensitive to drugs that inhibit protein translation, indicating disrupted ribosome function. Although the mechanism by which loss of ribosome function could promote cell transformation is not clear, the authors propose that, in Dkc1^m cells, translation of factors that regulate proliferation could be altered. Additional unrecognized functions of dyskerin could also exist, whereas reduced telomerase activty might contribute to later stages of tumour development.