title: A pathogenic dyskerin mutation impairs proliferation and activates a DNA damage response independent of telomere length in mice.
abstract: Telomeres are nucleoprotein structures that cap the ends of chromosomes, protecting them from exonucleases and distinguishing them from double-stranded breaks. Their integrity is maintained by telomerase, an enzyme consisting of a reverse transcriptase, TERT and an RNA template, TERC, and other components, including the pseudouridine synthase, dyskerin, the product of the DKC1 gene. When telomeres become critically short, a p53-dependent pathway causing cell cycle arrest is induced that can lead to senescence, apoptosis, or, rarely to genomic instability and transformation. The same pathway is induced in response to DNA damage. DKC1 mutations in the disease dyskeratosis congenita are thought to act via this mechanism, causing growth defects in proliferative tissues through telomere shortening. Here, we show that pathogenic mutations in mouse Dkc1 cause a growth disadvantage and an enhanced DNA damage response in the context of telomeres of normal length. We show by genetic experiments that the growth disadvantage, detected by disparities in X-inactivation patterns in female heterozygotes, depends on telomerase. Hemizygous male mutant cells showed a strikingly enhanced DNA damage response via the ATM/p53 pathway after treatment with etoposide with a significant number of DNA damage foci colocalizing with telomeres in cytological preparations. We conclude that dyskerin mutations cause slow growth independently of telomere shortening and that this slow growth is the result of the induction of DNA damage. Thus, dyskerin interacts with telomerase and affects telomere maintenance independently of telomere length.
authors.affiliation: Department of Medicine, Division of Hematology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Bai-Wei
authors.initials: BW
authors.lastname: Gu
authors.forename: Monica
authors.initials: M
authors.lastname: Bessler
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Mason
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005047:Etoposide / Q000633:toxicity; D005260:Female; D016158:Genes, p53; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D016615:Telomere / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C510431:Dkc1 protein, mouse; D009687:Nuclear Proteins; D005047:Etoposide