Impaired Control of IRES-Mediated Translation in X-Linked Dyskeratosis Congenita

Abstract

The DKC1 gene encodes a pseudouridine synthase that modifies ribosomal RNA (rRNA). DKC1 is mutated in people with X-linked dyskeratosis congenita (X-DC), a disease characterized by bone marrow failure, skin abnormalities, and increased susceptibility to cancer. How alterations in ribosome modification might lead to cancer and other features of the disease remains unknown. Using an unbiased proteomics strategy, we discovered a specific defect in IRES (internal ribosome entry site)-dependent translation in Dkc1(m) mice and in cells from X-DC patients. This defect results in impaired translation of messenger RNAs containing IRES elements, including those encoding the tumor suppressor p27(Kip1) and the antiapoptotic factors Bcl-xL and XIAP (X-linked Inhibitor of Apoptosis Protein). Moreover, Dkc1(m) ribosomes were unable to direct translation from IRES elements present in viral messenger RNAs. These findings reveal a potential mechanism by which defective ribosome activity leads to disease and cancer.

DKC1 overexpression associated with prostate cancer progression

“…It is noteworthy that we observed only a weak-to-moderate association between DKC1 levels and actual markers of tumour proliferation, such as MKI67 and PCNA, suggesting that the increase in DKC1 expression is not simply a by-product of enhanced cell proliferation. Dyskerin functions in several cellular processes, such as pseudouridine formation and consequently RNA and general protein biosynthesis (Filipowicz and Pogacic, 2002), biosynthesis of hTR, and stabilisation of the telomerase complex (Chang et al, 2002;Cohen et al, 2007), as well as regulation of apoptosis (Yoon et al, 2006). Downregulation of dyskerin by siRNA in prostate cancer cells did not elicit apoptosis by itself or sensitise to induction of apoptosis by TNF-a or tunicamycin, agents chosen because of their relevance to prostate cancer (Shiraishi et al, 2005).…”

“…To investigate the reported anti-apoptotic effect of dyskerin (Yoon et al, 2006) in prostate cancer cells, Du145 or 22Rv1 cells pretreated with siRNA for 3 days were challenged with apoptosis inducers TNF-a or tunicamycin (Shiraishi et al, 2005). The particular proapoptotic agents were chosen, because death receptor ligands such as TNF-a and endoplasmic reticulum stress, through which tunicamycin acts, are thought to be particularly important in prostate cancer.…”

“…The hTR RNA contains a specific recognition motif for dyskerin, and dyskerin is retained in the core telomerase complex (Chang et al, 2002;Cohen et al, 2007). Very recently, dyskerin was reported to exert an additional function by regulating the translation of a number of anti-apoptotic proteins (Yoon et al, 2006).…”

Publisher's Note

“…73 Similarly, loss of the pseuodouridine synthase Cbf5p in yeast also results in decreased tRNA binding, loss of translational fidelity, and reduction in IRES-mediated translation, phenotypes that are also evident in mouse and human cells upon loss of DKC1. 74,75 While there is mounting evidence that chemical modifications in rRNA are crucial to ribosome biogenesis and to maintenance of accurate and efficient protein synthesis, not the least of which is its strong conservation throughout evolution, many questions remain as to their mechanisms of action. As more details regarding rRNA modifications and the cellular machinery that controls them are revealed, however, we must take care in attributing function to the modifications themselves versus the enzymes that install them.…”

STAT1 Promotes KRAS Colon Tumor Growth and Susceptibility to Pharmacological Inhibition of Translation Initiation Factor eIF4A

“…27). To this end, we performed transient transfection assays of di-cistronic constructs bearing the 5 0 UTR of either BCL-XL or XIAP mRNA between the b-galactosidase and CAT reporter genes.…”