Gene Summary

Gene:DKC1; dyskerin pseudouridine synthase 1
Aliases: DKC, CBF5, DKCX, NAP57, NOLA4, XAP101
Summary:This gene functions in two distinct complexes. It plays an active role in telomerase stabilization and maintenance, as well as recognition of snoRNAs containing H/ACA sequences which provides stability during biogenesis and assembly into H/ACA small nucleolar RNA ribonucleoproteins (snoRNPs). This gene is highly conserved and widely expressed, and may play additional roles in nucleo-cytoplasmic shuttling, DNA damage response, and cell adhesion. Mutations have been associated with X-linked dyskeratosis congenita. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:H/ACA ribonucleoprotein complex subunit 4
Source:NCBIAccessed: 13 March, 2017


What does this gene/protein do?
Show (16)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Skin Cancer
  • Neoplasm Proteins
  • Bone Marrow
  • Cancer Gene Expression Regulation
  • siRNA
  • RNA, Ribosomal
  • Base Sequence
  • X Chromosome
  • Saccharomyces cerevisiae Proteins
  • Prostate Cancer
  • Mutation
  • Cell Cycle Proteins
  • Lung Cancer
  • Transfection
  • Gene Silencing
  • Oligonucleotide Array Sequence Analysis
  • Apoptosis
  • Immunohistochemistry
  • Tissue Banks
  • Western Blotting
  • Breast Cancer
  • Biomarkers, Tumor
  • Nuclear Proteins
  • Dyskeratosis Congenita
  • Retinoic Acid
  • Cell Proliferation
  • Colonic Neoplasms
  • Telomerase
  • p53 Protein
  • Tumor Suppressor Gene
  • Young Adult
  • Neoplastic Cell Transformation
  • Messenger RNA
  • Colorectal Cancer
  • HeLa Cells
  • Cancer RNA
  • Telomere
  • Genetic Predisposition
  • Gene Expression Profiling
  • Promoter Regions
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: DKC1 (cancer-related)

Takai H, Jenkinson E, Kabir S, et al.
A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus.
Genes Dev. 2016; 30(7):812-26 [PubMed] Free Access to Full Article Related Publications
Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1(CP)) in two siblings with CP. POT1(CP)induced a proliferative arrest that could be bypassed by telomerase. POT1(CP)was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1(CP)was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1(CP)was also defective in the maintenance of the telomeric C strand, causing extended 3' overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).

Panero J, Stella F, Schutz N, et al.
Differential Expression of Non-Shelterin Genes Associated with High Telomerase Levels and Telomere Shortening in Plasma Cell Disorders.
PLoS One. 2015; 10(9):e0137972 [PubMed] Free Access to Full Article Related Publications
Telomerase, shelterin proteins and various interacting factors, named non-shelterin proteins, are involved in the regulation of telomere length (TL). Altered expression of any of these telomere-associated genes can lead to telomere dysfunction, causing genomic instability and disease development. In this study, we investigated the expression profile of a set of non-shelterin genes involved in essential processes such as replication (RPA1), DNA damage repair pathways (MRE11-RAD50-NBS1) and stabilization of telomerase complex (DKC1), in 35 patients with monoclonal gammopathy of undetermined significance (MGUS) and 40 cases with multiple myeloma (MM). Results were correlated with hTERT expression, TL and clinical parameters. Overall, a significant increase in DKC1, RAD50, MRE11, NBS1 and RPA1 expression along with an upregulation of hTERT in MM compared with MGUS was observed (p≤0.032). Interestingly, in both entities high mRNA levels of non-shelterin genes were associated with short TLs and increased hTERT expression. Significant differences were observed for DKC1 in MM (p ≤0.026), suggesting an important role for this gene in the maintenance of short telomeres by telomerase in myeloma plasma cells. With regard to clinical associations, we observed a significant increase in DKC1, RAD50, MRE11 and RPA1 expression in MM cases with high bone marrow infiltration (p≤0.03) and a tendency towards cases with advanced ISS stage, providing the first evidence of non-shelterin genes associated to risk factors in MM. Taken together, our findings bring new insights into the intricate mechanisms by which telomere-associated proteins collaborate in the maintenance of plasma cells immortalization and suggest a role for the upregulation of these genes in the progression of the disease.

Penzo M, Ludovini V, Treré D, et al.
Dyskerin and TERC expression may condition survival in lung cancer patients.
Oncotarget. 2015; 6(25):21755-60 [PubMed] Free Access to Full Article Related Publications
Dyskerin mediates both the modification of uridine on ribosomal and small nuclear RNAs and the stabilization of the telomerase RNA component (TERC). In human tumors dyskerin expression was found to be associated with both rRNA modification and TERC levels. Moreover, dyskerin overexpression has been linked to unfavorable prognosis in a variety of tumor types, however an explanation for the latter association is not available. To clarify this point, we analyzed the connection between dyskerin expression, TERC levels and clinical outcome in two series of primary lung cancers, differing for the presence of TERC gene amplification, a genetic alteration inducing strong TERC overexpression. TERC levels were significantly higher in tumors bearing TERC gene amplification (P = 0.017). In addition, the well-established association between dyskerin expression and TERC levels was observed only in the series without TERC gene amplification (P = 0.003), while it was not present in TERC amplified tumors (P = 0.929). Similarly, the association between dyskerin expression and survival was found in cases not bearing TERC gene amplification (P = 0.009) and was not observed in TERC amplified tumors (P = 0.584). These results indicate that the influence of dyskerin expression on tumor clinical outcome is linked to its role on the maintenance of high levels of TERC.

Babushok DV, Bessler M
Genetic predisposition syndromes: when should they be considered in the work-up of MDS?
Best Pract Res Clin Haematol. 2015; 28(1):55-68 [PubMed] Free Access to Full Article Related Publications
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by cytopenias, ineffective hematopoiesis, myelodysplasia, and an increased risk of acute myeloid leukemia (AML). While sporadic MDS is primarily a disease of the elderly, MDS in children and young and middle-aged adults is frequently associated with underlying genetic predisposition syndromes. In addition to the classic hereditary bone marrow failure syndromes (BMFS) such as Fanconi Anemia and Dyskeratosis Congenita, in recent years there has been an increased awareness of non-syndromic familial MDS/AML predisposition syndromes such as those caused by mutations in GATA2, RUNX1, CEBPA, and SRP72 genes. Here, we will discuss the importance of recognizing an underlying genetic predisposition syndrome a patient with MDS, will review clinical scenarios when genetic predisposition should be considered, and will provide a practical overview of the common BMFS and familial MDS/AML syndromes which may be encountered in adult patients with MDS.

Zhang MY, Keel SB, Walsh T, et al.
Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity.
Haematologica. 2015; 100(1):42-8 [PubMed] Free Access to Full Article Related Publications
Accurate and timely diagnosis of inherited bone marrow failure and inherited myelodysplastic syndromes is essential to guide clinical management. Distinguishing inherited from acquired bone marrow failure/myelodysplastic syndrome poses a significant clinical challenge. At present, diagnostic genetic testing for inherited bone marrow failure/myelodysplastic syndrome is performed gene-by-gene, guided by clinical and laboratory evaluation. We hypothesized that standard clinically-directed genetic testing misses patients with cryptic or atypical presentations of inherited bone marrow failure/myelodysplastic syndrome. In order to screen simultaneously for mutations of all classes in bone marrow failure/myelodysplastic syndrome genes, we developed and validated a panel of 85 genes for targeted capture and multiplexed massively parallel sequencing. In patients with clinical diagnoses of Fanconi anemia, genomic analysis resolved subtype assignment, including those of patients with inconclusive complementation test results. Eight out of 71 patients with idiopathic bone marrow failure or myelodysplastic syndrome were found to harbor damaging germline mutations in GATA2, RUNX1, DKC1, or LIG4. All 8 of these patients lacked classical clinical stigmata or laboratory findings of these syndromes and only 4 had a family history suggestive of inherited disease. These results reflect the extensive genetic heterogeneity and phenotypic complexity of bone marrow failure/myelodysplastic syndrome phenotypes. This study supports the integration of broad unbiased genetic screening into the diagnostic workup of children and young adults with bone marrow failure and myelodysplastic syndromes.

Townsley DM, Dumitriu B, Young NS
Bone marrow failure and the telomeropathies.
Blood. 2014; 124(18):2775-83 [PubMed] Free Access to Full Article Related Publications
Our understanding of the pathophysiology of aplastic anemia is undergoing significant revision, with implications for diagnosis and treatment. Constitutional and acquired disease is poorly delineated, as lesions in some genetic pathways cause stereotypical childhood syndromes and also act as risk factors for clinical manifestations in adult life. Telomere diseases are a prominent example of this relationship. Accelerated telomere attrition is the result of mutations in telomere repair genes and genes encoding components of the shelterin complex and related proteins. Genotype-phenotype correlations show genes responsible for X-linked (DKC1) and severe recessive childhood dyskeratosis congenita, typically with associated mucocutaneous features, and others (TERC and TERT) for more subtle presentation as telomeropathy in adults, in which multiorgan failure may be prominent. Telomerase mutations also are etiologic in familial pulmonary fibrosis and cryptic liver disease. Detection of a telomere disease requires awareness in the clinic, appropriate laboratory testing of telomere content, and genetic sequencing. In treatment decisions, genetic screening of related donors for hematopoietic stem cell transplantation is critical, and androgen therapy may be helpful. Telomeres shorten normally with aging, as well as under environmental circumstances, with regenerative stress and oxidative damage. Telomere biology is complexly related to oncogenesis: telomere attrition is protective by enforcing senescence or apoptosis in cells with a long mitotic history, but telomere loss also can destabilize the genome by chromosome rearrangement and aneuploidy.

Lin P, Mobasher ME, Alawi F
Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis.
Biochem Biophys Res Commun. 2014; 446(4):1268-75 [PubMed] Free Access to Full Article Related Publications
Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita (DC). Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines. However, the mechanisms remained unclear. Using human U2OS osteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescence as evidenced by proliferative arrest, senescence-associated heterochromatinization and a senescence-associated molecular profile. Senescence can render cells resistant to apoptosis. Conversely, chromatin relaxation can reverse the repressive effects of senescence-associated heterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis was suppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation, including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitized dyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex and plays an important role in telomere homeostasis. Defective telomere maintenance resulting in premature senescence is thought to primarily underlie the pathogenesis of X-linked DC. Since U2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function can also induce cellular senescence via mechanisms independent of telomere shortening.

Powell JB, Dokal I, Carr R, et al.
X-linked dyskeratosis congenita presenting in adulthood with photodamaged skin and epiphora.
Clin Exp Dermatol. 2014; 39(3):310-4 [PubMed] Related Publications
Dyskeratosis congenita (DC) is a clinically and genetically heterogeneous multisystem bone marrow failure disorder of telomere maintenance, which may present with dermatological features. The main cause of mortality is bone marrow failure, often developing in the second decade of life, although pulmonary disease and malignancies such as squamous cell carcinomas (SCCs) may also prove fatal. We report the case of a 28-year-old man with X-linked DC and confirmed DKC1 gene mutation. In addition to the classic triad of nail dystrophy, hyperpigmentation and oral leucoplakia, the patient had actinic keratosis (AK) and photodamaged skin, hitherto under-recognized features of this condition. Awareness of the clinical presentation of DC is important, as accurate clinical and molecular diagnosis affords patients and their families genetic counselling, cancer prevention and screening measures, and planning for complications such as bone marrow failure.

Chen LY, Majerská J, Lingner J
Molecular basis of telomere syndrome caused by CTC1 mutations.
Genes Dev. 2013; 27(19):2099-108 [PubMed] Free Access to Full Article Related Publications
Mutations in CTC1 lead to the telomere syndromes Coats Plus and dyskeratosis congenita (DC), but the molecular mechanisms involved remain unknown. CTC1 forms with STN1 and TEN1 a trimeric complex termed CST, which binds ssDNA, promotes telomere DNA synthesis, and inhibits telomerase-mediated telomere elongation. Here we identify CTC1 disease mutations that disrupt CST complex formation, the physical interaction with DNA polymerase α-primase (polα-primase), telomeric ssDNA binding in vitro, accumulation in the nucleus, and/or telomere association in vivo. While having diverse molecular defects, CTC1 mutations commonly lead to the accumulation of internal single-stranded gaps of telomeric DNA, suggesting telomere DNA replication defects as a primary cause of the disease. Strikingly, mutations in CTC1 may also unleash telomerase repression and telomere length control. Hence, the telomere defect initiated by CTC1 mutations is distinct from the telomerase insufficiencies seen in classical forms of telomere syndromes, which cause short telomeres due to reduced maintenance of distal telomeric ends by telomerase. Our analysis provides molecular evidence that CST collaborates with DNA polα-primase to promote faithful telomere DNA replication.

Batista LF, Artandi SE
Understanding telomere diseases through analysis of patient-derived iPS cells.
Curr Opin Genet Dev. 2013; 23(5):526-33 [PubMed] Free Access to Full Article Related Publications
A unique characteristic of tissue stem cells is the ability to self-renew, a process that enables the life-long maintenance of many organs. Stem cell self-renewal is dependent in part on the synthesis of telomere repeats by the enzyme telomerase. Defects in telomerase and in genes in the telomere maintenance pathway result in diverse disease states, including dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, liver cirrhosis and cancer. Many of these disease states share a tissue failure phenotype, such as loss of bone marrow cells or failure of pulmonary epithelium, suggesting that stem cell dysfunction is a common pathophysiological mechanism underlying these telomere diseases. Studies of telomere diseases in undifferentiated iPS cells have provided a quantitative relationship between the magnitude of biochemical defects in the telomerase pathway and disease severity in patients, thereby establishing a clear correlation between genotype and phenotype in telomere disease states. Modeling telomere diseases in iPS cells has also revealed diverse underlying disease mechanisms, including reduced telomerase catalytic activity, diminished assembly of the telomerase holoenzyme and impaired trafficking of the enzyme within the nucleus. These studies highlight the need for therapies tailored to the underlying biochemical defect in each class of patients.

Hartwig FP, Collares T
Telomere dysfunction and tumor suppression responses in dyskeratosis congenita: balancing cancer and tissue renewal impairment.
Ageing Res Rev. 2013; 12(2):642-52 [PubMed] Related Publications
Dyskeratosis congenita (DC) encompasses a large spectrum of diseases and clinical manifestations generally related to premature aging, including bone marrow failure and cancer predisposition. The major risk factor for DC is to carry germline telomere-related mutations - in telomerase or telomere shelterin genes - which results in premature telomere dysfunction, thus increasing the risk of premature aging impairments. Despite the advances that have been accomplished in DC research, the molecular aspects underlying the phenotypic variability of the disease remain poorly understood. Here different aspects of telomere biology, concerning adult stem cells senescence, tumor suppression and cancer are considered in the context of DC, resulting in two translational models: late onset of DC symptoms in telomere-related mutations carriers is a potential indicator of increased cancer risk and differences in tumor suppression capacities among the genetic subgroups are (at least partial) causes of different clinical manifestations of the disease. The limitations of both models are presented, and further experiments for their validation, as well as clinical implications, are discussed.

Penzo M, Casoli L, Ceccarelli C, et al.
DKC1 gene mutations in human sporadic cancer.
Histol Histopathol. 2013; 28(3):365-72 [PubMed] Related Publications
INTRODUCTION: Germline mutations in the tumour suppressor gene dyskeratosis congenit 1 (DKC1) cause the cancer prone syndrome called X-linked dyskeratosis congenita. The present study aims to determine whether mutations of the DKC1 gene may also be present in frequent human sporadic cancers (breast, colon and lung cancers), thus potentially contributing to the neoplastic phenotype.
MATERIALS AND METHODS: mutation analysis of the DKC1 gene was performed on DNA from 110 primary human lung, 54 breast, and 35 colon cancers, focusing on gene regions where pathogenic germline mutations have been described previously (promoter and exons 1, 3, 9, 10, 11, and 14).
RESULTS: Out of a total of 199 primary tumours of different origins, only 5 turned out to have sequence variations in the DKC1 gene. These variations were of two kinds, C8120T and C13554T, which are both classified as synonymous mutations and do not affect DKC1 mRNA splicing.
CONCLUSION: direct DKC1 gene mutations are not a frequent event in tumourigenesis, at least in the tumour types investigated and for the DKC1 gene portions considered in this study.

Bohn OL, Whitten J, Spitzer B, et al.
Posttransplant lymphoproliferative disorder complicating hematopoietic stem cell transplantation in a patient with dyskeratosis congenita.
Int J Surg Pathol. 2013; 21(5):520-5 [PubMed] Related Publications
Dyskeratosis congenita (DC) is a rare inherited disorder characterized by bone marrow failure and cancer predisposition. We present a case of a 28-year-old woman with DC who was admitted for hematopoietic stem cell transplantation (HSCT) for aplastic anemia and who developed acute myeloid leukemia with complex genetic karyotype abnormalities including the MLL (11q23) gene, 1q25, and chromosome 8. After transplantation, a monomorphic Epstein-Barr virus (EBV) negative posttransplant-associated lymphoproliferative disorder (PTLD) diffuse large B-cell lymphoma was discovered involving the liver, omental tissue, and peritoneal fluid samples showing additional MLL (11q23) gene abnormalities by fluorescence in situ hybridization. Despite treatment, the patient died of complications associated with transplantation and invasive fungal infection. This case represents the first bona fide documented case of EBV-negative monomorphic PTLD host derived, with MLL gene abnormalities in a patient with DC, and shows another possible mechanism for the development of a therapy-related lymphoid neoplasm after transplantation.

Liu B, Zhang J, Huang C, Liu H
Dyskerin overexpression in human hepatocellular carcinoma is associated with advanced clinical stage and poor patient prognosis.
PLoS One. 2012; 7(8):e43147 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dyskerin (encoded by the DKC1 gene) is an essential nucleolar protein involved in cell proliferation, where it is required for the pseudo-uridylation of ribosomal RNA (rRNA) molecules and the stabilization of the telomerase RNA component. Dyskerin expression has been reported to predict poor survival in some cancer patients. The aim of the present study was to analyze the expression of dyskerin in hepatocellular carcinoma (HCC) and to determine its correlation with clinicopathologic features, including the survival of patients with HCC.
METHODOLOGY/PRINCIPAL FINDINGS: Dyskerin protein expression was detected by immunohistochemistry in paraffin sections of 252 HCC cases and 80 noncancerous liver tissues. The correlation was analyzed between dyskerin expression levels and clinicopathologic variables and prognosis. Dyskerin protein was significantly overexpressed in HCC tissues when compared to noncancerous liver tissue. Dyskerin overexpression was positively correlated with the hepatitis B surface antigen status, serum alpha-fetoprotein, and advanced clinical stage in HCC patients. A survival analysis indicated that HCC patients with higher dyskerin expression had a significantly shorter overall survival and 5-year survival time when compared to those with low expression. A multivariate analysis suggested that dyskerin overexpression was an independent factor for prognosis (hazard risk, 2.912; P = 0.007). Expression of DKC1 mRNA was measured by quantitative RT-PCR in 80 HCC and 50 non-cancerous tissues. The relationship between DKC1, TERT, MKI67, and MYC mRNA expression in HCC tissues was also evaluated. DKC1 mRNA was significantly overexpressed in HCC tissues and showed a significant correlation with MKI67 and MYC mRNA but a weak correlation with TERT mRNA.
CONCLUSIONS/SIGNIFICANCE: Dyskerin overexpression in HCC patients was correlated with MYC and MKI67 expression and showed a possible involvement in the tumorigenic process. Dyskerin overexpression may be an unfavorable prognostic factor in patients with HCC.

Young NS
Bone marrow failure and the new telomere diseases: practice and research.
Hematology. 2012; 17 Suppl 1:S18-21 [PubMed] Related Publications
The telomeropathies are a newly described group of human diseases based on the genetics and molecular biology of the telomeres, the ends of chromosomes. Telomeres are repeated hexanucleotides and their associated proteins; the protect chromosomes from recognition as damaged DNA, and their inevitable gradual loss with DNA replication is harmless as they are noncoding. However, when telomeres become critically short in a cell, senescence, apoptosis, or, rarely malignant transformation results. In individuals with mutations in genes involved in telomere repair, especially the enzymatic telomerase complex, telomere attrition is accelerated. Severe deficiencies result in dyskeratosis congenita, a congenital aplastic anemia with associated mucocutaneous abnormalities. Mutations in TERT, the catalytic component, and TERC, the RNA template, can behave as risk factors for the development of bone marrow failure, pulmonary fibrosis, and hepatic cirrhosis. Both penetrance and organ specificity are variable and not well understood. Chromosome instability is a result of critical shortening of telomeres and cancer. For example, short telomeres are the major prognostic risk factor for clonal evolution to myelodysplasia and acute leukemia. Practically, hematologists need to recognize the multisystem presentation of telomere disease, implications for outcomes, and options for therapy.

Aalbers AM, Kajigaya S, van den Heuvel-Eibrink MM, et al.
Human telomere disease due to disruption of the CCAAT box of the TERC promoter.
Blood. 2012; 119(13):3060-3 [PubMed] Free Access to Full Article Related Publications
Mutations in the coding region of telomerase complex genes can result in accelerated telomere attrition and human disease. Manifestations of telomere disease include the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia, acute myeloid leukemia, liver cirrhosis, and pulmonary fibrosis. Here, we describe a mutation in the CCAAT box (GCAAT) of the TERC gene promoter in a family in which multiple members had typical features of telomeropathy. The genetic alteration in this critical regulatory sequence resulted in reduced reporter gene activity and absent binding of transcription factor NF-Y, likely responsible for reduced TERC levels, decreased telomerase activity, and short telomeres. This is the first description of a pathogenic mutation in the highly conserved CCAAT box and the first instance of a mutation in the promoter region of TERC producing a telomeropathy. We propose that current mutation-screening strategies should include gene promoter regions for the diagnosis of telomere diseases. This clinical trial was registered at as #NCT00071045.

Nallar SC, Lin L, Srivastava V, et al.
GRIM-1, a novel growth suppressor, inhibits rRNA maturation by suppressing small nucleolar RNAs.
PLoS One. 2011; 6(9):e24082 [PubMed] Free Access to Full Article Related Publications
We have recently isolated novel IFN-inducible gene, Gene associated with Retinoid-Interferon-induced Mortality-1 (GRIM-1), using a genetic technique. Moderate ectopic expression of GRIM-1 caused growth inhibition and sensitized cells to retinoic acid (RA)/IFN-induced cell death while high expression caused apoptosis. GRIM-1 depletion, using RNAi, conferred a growth advantage. Three protein isoforms (1α, 1β and 1γ) with identical C-termini are produced from GRIM-1 mRNA. We show that GRIM-1 isoforms interact with NAF1 and DKC1, two essential proteins required for box H/ACA sno/sca RNP biogenesis and suppresses box H/ACA RNA levels in mammalian cells by delocalizing NAF1. Suppression of these small RNAs manifests as inefficient rRNA maturation and growth suppression. Interestingly, yeast Shq1p also caused growth suppression in mammalian cells. Consistent with its growth-suppressive property, GRIM-1 expression is lost in a number of human primary prostate tumors. Our observations support a recent study that GRIM-1 might act as a co-tumor suppressor in the prostate.

Martinez-Delgado B, Yanowsky K, Inglada-Perez L, et al.
Genetic anticipation is associated with telomere shortening in hereditary breast cancer.
PLoS Genet. 2011; 7(7):e1002182 [PubMed] Free Access to Full Article Related Publications
There is increasing evidence suggesting that short telomeres and subsequent genomic instability contribute to malignant transformation. Telomere shortening has been described as a mechanism to explain genetic anticipation in dyskeratosis congenita and Li-Fraumeni syndrome. Since genetic anticipation has been observed in familial breast cancer, we aimed to study telomere length in familial breast cancer patients and hypothesized that genetic defects causing this disease would affect telomere maintenance resulting in shortened telomeres. Here, we first investigated age anticipation in mother-daughter pairs with breast cancer in 623 breast cancer families, classified as BRCA1, BRCA2, and BRCAX. Moreover, we analyzed telomere length in DNA from peripheral blood leukocytes by quantitative PCR in a set of 198 hereditary breast cancer patients, and compared them with 267 control samples and 71 sporadic breast cancer patients. Changes in telomere length in mother-daughter pairs from breast cancer families and controls were also evaluated to address differences through generations. We demonstrated that short telomeres characterize hereditary but not sporadic breast cancer. We have defined a group of BRCAX families with short telomeres, suggesting that telomere maintenance genes might be susceptibility genes for breast cancer. Significantly, we described that progressive telomere shortening is associated with earlier onset of breast cancer in successive generations of affected families. Our results provide evidence that telomere shortening is associated with earlier age of cancer onset in successive generations, suggesting that it might be a mechanism of genetic anticipation in hereditary breast cancer.

Alawi F, Lin P, Ziober B, Patel R
Correlation of dyskerin expression with active proliferation independent of telomerase.
Head Neck. 2011; 33(7):1041-51 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dyskerin, which is an important component of the telomerase complex and is needed for normal telomerase activity, is frequently overexpressed in neoplasia. Dyskerin also plays an essential role in ribosome biogenesis. Because protein synthesis increases during tumorigenesis, this led us to hypothesize that dyskerin expression would be upregulated independently of the cell immortalization mechanism.
METHODS: Dyskerin and telomerase reverse transcriptase (TERT) expression were examined in oral squamous cell carcinomas (OSCC) and patient-matched controls, as well as in a panel of telomerase-positive and telomerase-negative cells. Antisense inhibition of TERT was used to test the effects of downregulation of telomerase on dyskerin expression.
RESULTS: Dyskerin was frequently overexpressed in OSCC and in immortalized and transformed keratinocytes relative to primary cells, independently of TERT and telomerase activity. Instead, dyskerin expression strongly correlated with cell proliferation rates.
CONCLUSIONS: The role of dyskerin in tumorigenesis does not correlate with its function within the telomerase complex.

Lee YP, Chao SC, Lee JY
Naevus anaemicus-like hypopigmented macules in dyskeratosis congenita.
Australas J Dermatol. 2011; 52(2):142-5 [PubMed] Related Publications
In the present paper we report on a Taiwanese case of X-linked recessive dyskeratosis congenita (DC), confirmed by detection of a 214 C→T mutation in the DKC1 gene, and provide a detailed description of mottled pigmentary changes of the skin, specifically numerous small, whitish macules dispersed against a background of diffuse, finely reticulated hyperpigmentation. The hypopigmented macules showed no discernible erythema upon rubbing or the local application of heat. The naevus anaemicus-like macules may be a relatively common but under-recognized feature in DC. More studies are required to determine the incidence and histopathology of these macules.

Watanabe A, Tagawa H, Yamashita J, et al.
The role of microRNA-150 as a tumor suppressor in malignant lymphoma.
Leukemia. 2011; 25(8):1324-34 [PubMed] Related Publications
MicroRNA (miRNA; miR) is a class of small regulatory RNA molecules, the aberrant expression of which can lead to the development of cancer. We recently reported that overexpression of miR-21 and/or miR-155 leads to activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway in malignant lymphomas expressing CD3(-)CD56(+) natural killer (NK) cell antigen. Through expression analysis, we show in this study that in both NK/T-cell lymphoma lines and samples of primary lymphoma, levels of miR-150 expression are significantly lower than in normal NK cells. To examine its role in lymphomagenesis, we transduced miR-150 into NK/T-cell lymphoma cells, which increased the incidence of apoptosis and reduced cell proliferation. Moreover, the miR-150 transductants appeared senescent and showed lower telomerase activity, resulting in shortened telomeric DNA. We also found that miR-150 directly downregulated expression of DKC1 and AKT2, reduced levels of phosphorylated AKT(ser473/4) and increased levels of tumor suppressors such as Bim and p53. Collectively, these results suggest that miR-150 functions as a tumor suppressor, and that its aberrant downregulation induces continuous activation of the PI3K-AKT pathway, leading to telomerase activation and immortalization of cancer cells. These findings provide new insight into the pathogenesis of malignant lymphoma.

Montanaro L
Dyskerin and cancer: more than telomerase. The defect in mRNA translation helps in explaining how a proliferative defect leads to cancer.
J Pathol. 2010; 222(4):345-9 [PubMed] Related Publications
Point mutations in the DKC1 gene that encodes dyskerin cause the rare inherited syndrome called X-linked dyskeratosis congenita, characterized by a failure of proliferating tissues and increased susceptibility to cancer. Dyskerin is a nucleolar protein with different functions, all fundamental to basic cellular events such as protein expression, growth, and proliferation. The two best-characterized dyskerin activities are the stabilization of the telomerase RNA component, allowing the proper function telomerase enzymatic complex, and the modification of specific uridine residues of ribosomal RNA by converting them to pseudouridine, thus allowing proper ribosome processing and function. In light of the recent findings, this review focuses on the molecular pathogenesis of dyskeratosis congenita, discussing how a defect in ribosomal function might impact on the translation of a subset of mRNAs encoding for tumour suppressors, thus providing an explanation for the apparent paradox of dyskeratosis congenita in which reduced cell proliferation is associated with cancer susceptibility. In addition, the current evidence pointing to a role played by dyskerin in tumours in the general population is also discussed.

Koskimaa HM, Kurvinen K, Costa S, et al.
Molecular markers implicating early malignant events in cervical carcinogenesis.
Cancer Epidemiol Biomarkers Prev. 2010; 19(8):2003-12 [PubMed] Related Publications
BACKGROUND: Human papillomavirus can induce a stepwise progression of precursor lesions to carcinoma. Sensitive and specific molecular markers are needed to identify the cervical lesions (CIN) at risk for this progression. hTERT activation could be one indicator of a point of no return in malignant progression.
METHODS: The UT-DEC-1 cell line is an in vitro model for the study of human papillomavirus-induced progression. Using molecular mining, nine potential genes interlinking hTERT and viral oncogene expression with the phenotypical features of CIN2 were identified. After preliminary testing with real-time PCR, five genes were selected for further analysis: hTERT, DKC1, Bcl-2, S100A8, and S100A9. These proteins were also tested in a series of 120 CIN lesions using immunohistochemistry.
RESULTS: Analysis of the mRNA expression of these genes at different cell passages revealed three time points with significant changes. hTERT, Bcl-2, and S100A9 were also overexpressed in CIN lesions, and the expression pattern changed during the progression toward CIN3 lesions.
CONCLUSIONS: These identified time points that were combined with the mRNA overexpression of target genes matched events previously shown to be important in the progression toward malignancy: (a) the viral integration into the cell genome and episome loss; (b) the selection of cells with an acquired growth advantage and ability to maintain telomerase activity; and (c) the final stage of malignancy with permanently upregulated telomerase.
IMPACT: hTERT, Bcl-2, and S100A9 together might compose a potential prognostic marker panel for the assessment of CIN lesions. These results, however, need further validation in prospective clinical settings. (c)2010 AACR.

Bellodi C, Krasnykh O, Haynes N, et al.
Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis.
Cancer Res. 2010; 70(14):6026-35 [PubMed] Free Access to Full Article Related Publications
Mutations in DKC1, encoding for dyskerin, a pseudouridine synthase that modifies rRNA and regulates telomerase activity, are associated with ribosomal dysfunction and increased cancer susceptibility in the human syndrome, X-linked dyskeratosis congenita (X-DC). In a mouse model for X-DC, impairments in DKC1 function affected the translation of specific mRNAs harboring internal ribosomal entry site (IRES) elements, including the tumor suppressor, p27. However, how this translational deregulation contributes to tumor initiation and progression remains poorly understood. Here, we report that impairment in p27 IRES-mediated translation due to decreased levels of DKC1 activity markedly increases spontaneous pituitary tumorigenesis in p27 heterozygous mice. Using a new bioluminescent mouse model, we monitored p27 translation in vivo and show that p27 IRES-mediated translation is reduced in the pituitary of DKC1 hypomorphic mice (DKC1(m)). Furthermore, we show that DKC1 has a critical role in regulating the assembly of the 48S translational preinitiation complex mediated by the p27 IRES element. An analysis of human tumors identified a novel mutation of DKC1 (DKC1(S485G)) in a human pituitary adenoma. We show that this specific amino acid substitution significantly alters DKC1 stability/pseudouridylation activity, and this correlates with reductions in p27 protein levels. Furthermore, DKC1(S485G) mutation does not alter telomerase RNA levels. Altogether, these findings show that genetic alterations in DKC1 could contribute to tumorigenesis associated with somatic cancers and establish a critical role for DKC1 in tumor suppression, at least in part, through translational control of p27.

Montanaro L, Calienni M, Bertoni S, et al.
Novel dyskerin-mediated mechanism of p53 inactivation through defective mRNA translation.
Cancer Res. 2010; 70(11):4767-77 [PubMed] Related Publications
In up to 60% of human cancers, p53 gene mutations are responsible for direct inactivation of the tumor suppressor function of p53. Alternative mechanisms of p53 inactivation described thus far mainly affect its posttranslational regulation. In X-linked dyskeratosis congenita, a multisystemic syndrome characterized by increased cancer susceptibility, mutations of the DKC1 gene encoding dyskerin cause a selective defect in the translation of a subgroup of internal ribosome entry site (IRES)-containing cellular mRNAs. In this study, we show that impairment of dyskerin function can cause p53 inactivation due to a defect in p53 mRNA translation. siRNA-mediated reduction of dyskerin levels caused a decrease of p53 mRNA translation, protein levels, and functional activity, both in human breast cancer cells and in primary mammary epithelial progenitor cells. These effects seemed to be independent of the known role of dyskerin in telomerase function, and they were associated with a specific impairment of translation initiation mediated by IRES elements present in p53 mRNA. In a series of human primary breast cancers retaining wild-type p53, we found that low levels of dyskerin expression were associated with reduced expression of p53-positive target genes. Our findings suggest that a dyskerin-mediated mechanism of p53 inactivation may occur in a subset of human tumors.

Tamary H, Nishri D, Yacobovich J, et al.
Frequency and natural history of inherited bone marrow failure syndromes: the Israeli Inherited Bone Marrow Failure Registry.
Haematologica. 2010; 95(8):1300-7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Inherited bone marrow failure syndromes are rare genetic disorders characterized by bone marrow failure, congenital anomalies, and cancer predisposition. Available single disease registries provide reliable information regarding natural history, efficacy and side effects of treatments, and contribute to the discovery of the causative genes. However, these registries could not shed light on the true incidence of the various syndromes. We, therefore, established an Israeli national registry in order to investigate the relative frequency of each of these syndromes and their complications.
DESIGN AND METHODS: Patients were registered by their hematologists in all 16 medical centers in Israel. We included patients with Fanconi anemia, severe congenital neutropenia, Diamond-Blackfan anemia, congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita, Shwachman-Diamond syndrome, and thrombocytopenia with absent radii.
RESULTS: One hundred and twenty-seven patients diagnosed between 1966 and 2007 were registered. Fifty-two percent were found to have Fanconi anemia, 17% severe congenital neutropenia, 14% Diamond-Blackfan anemia, 6% congenital amegakaryocytic thrombocytopenia, 5% dyskeratosis congenita, 2% Shwachman-Diamond syndrome, and 2% thrombocytopenia with absent radii. No specific diagnosis was made in only 2 patients. Of the thirty patients (24%) developing severe bone marrow failure, 80% had Fanconi anemia. Seven of 9 patients with leukemia had Fanconi anemia, as did all 6 with solid tumors. Thirty-four patients died from their disease; 25 (74%) had Fanconi anemia and 6 (17%) had severe congenital neutropenia.
CONCLUSIONS: This is the first comprehensive population-based study evaluating the incidence and complications of the different inherited bone marrow failure syndromes. By far the most common disease was Fanconi anemia, followed by severe congenital neutropenia and Diamond-Blackfan anemia. Fanconi anemia carried the worst prognosis, with severe bone marrow failure and cancer susceptibility. Diamond-Blackfan anemia had the best prognosis. The data presented provide a rational basis for prevention programs and longitudinal surveillance of the complications of inherited bone marrow failure syndromes.

Smith IM, Mithani SK, Mydlarz WK, et al.
Inactivation of the tumor suppressor genes causing the hereditary syndromes predisposing to head and neck cancer via promoter hypermethylation in sporadic head and neck cancers.
ORL J Otorhinolaryngol Relat Spec. 2010; 72(1):44-50 [PubMed] Free Access to Full Article Related Publications
Fanconi anemia (FA) and dyskeratosis congenita (DC) are rare inherited syndromes that cause head and neck squamous cell cancer (HNSCC). Prior studies of inherited forms of cancer have been extremely important in elucidating tumor suppressor genes inactivated in sporadic tumors. Here, we studied whether sporadic tumors have epigenetic silencing of the genes causing the inherited forms of HNSCC. Using bisulfite sequencing, we investigated the incidence of promoter hypermethylation of the 17 Fanconi- and DC-associated genes in sporadic HNSCC. Genes that only showed methylation in the tumor patients were chosen for quantitative methylation-specific PCR (qMSP) in a set of 45 tumor and 16 normal patients. Three gene promoters showed differences in methylation: FancB (FAAP95, FA core complex), FancJ (BRIP1, DNA Helicase/ATPase), and DKC1 (dyskeratin). Bisulfite sequencing revealed that only FancB and DKC1 showed no methylation in normal patients, yet the presence of promoter hypermethylation in tumor patients. On qMSP, 1/16 (6.25%) of the normal mucosal samples from non-cancer patients and 14/45 (31.1%) of the tumor patients demonstrated hypermethylation of the FancB locus (p < 0.05). These results suggest that inactivation of FancB may play a role in the pathogenesis of sporadic HNSCC.

Witkowska A, Gumprecht J, Glogowska-Ligus J, et al.
Expression profile of significant immortalization genes in colon cancer.
Int J Mol Med. 2010; 25(3):321-9 [PubMed] Related Publications
Cancer is a disease of genomic instability, a multistep process involving numerous mutations and chromosomal aberrations. Telomeres are highly specialized structures at the ends of chromosomes and function to stabilize and protect the ends of linear chromosomes, therefore determining cellular immortalization. Homeostasis of telomere length is a multifactor-dependent process. Since cellular immortalization is an early and essential step towards cancer, the aim of the present study was to determine immortalization genes that are significant in colon cancer and assess their usefulness in the early diagnosis of this tumor. Expression profiles of 119 transcripts known to be involved in cellular immortalization were assessed with oligonucleotide microarrays in 13 probes of colon adenocarcinoma (low and high clinical stages) and 9 probes of controls (normal colon tissue) and were compared among these groups with the use of the Significant Analysis Microarray (SAM) software and independently verified with the effect size parameter. Eighteen genes with significantly differential expression between high clinical stage colon cancer and the control group, and 21 with differential expression between low clinical stage colon cancer and the control group were identified. Nine genes showing altered expression in both low and high clinical stage colon cancer: ACD (TPP1), DKC1 and ERCC1, MYC, MAX, NBN, NOLA2, PRKDC and HSP82 should, in particular, be the subjects of further studies including QRT-PCR methods.

Calado RT
Telomeres and marrow failure.
Hematology Am Soc Hematol Educ Program. 2009; :338-43 [PubMed] Related Publications
Telomeres, repeat sequences at the ends of chromosomes, are protective chromosomal structures highly conserved from primitive organisms to humans. Telomeres inevitably shorten with every cell cycle, and telomere attrition has been hypothesized to be fundamental to normal senescence of cells, tissues, and organisms. Molecular mechanisms have evolved to maintain their length and protective function; telomerase (TERT) is a reverse transcriptase enzyme that uses an RNA molecule (TERC) as the template to elongate the 3' ends of telomeres. Shelterin is a collection of DNA-binding proteins that cover and protect telomeres. The recent discovery of inherited mutations in genes that function to repair telomeres as etiologic in a range of human diseases, which have clinical manifestations in diverse tissues, including the hematopoietic tissue, suggests that defects in telomere repair and protection can cause organ failure. Dyskeratosis congenita is the prototype of telomere diseases; it is characterized by bone marrow failure, mucocutaneous abnormalities, pulmonary fibrosis, liver cirrhosis, and increased susceptibility to cancer, including acute myeloid leukemia. Aplastic anemia, acute myeloid leukemia, and idiopathic pulmonary fibrosis also are associated with inherited mutations in telomere repair or protection genes. Additionally, telomere defects associate with predisposition to hematologic malignancy and epithelial tumors. Telomere erosion is abnormally rapid in patients with mutations in telomerase genes but also after hematopoietic stem cell transplant, and telomeres are naturally shorter in older individuals-all conditions associated with higher rates of malignant diseases. In human tissue culture, short telomeres produce end-to-end chromosome fusion, nonreciprocal translocations, and aneuploidy.

Perona R, Machado-Pinilla R, Manguan C, Carrillo J
Telomerase deficiency and cancer susceptibility syndromes.
Clin Transl Oncol. 2009; 11(11):711-4 [PubMed] Related Publications
Telomeres from most eukaryotes are composed of repeats of guanine-rich sequences whose main function is to preserve the end of the chromosomes. Telomeres are synthesised by a reverse transcriptase enzyme, telomerase (TERT), which forms part of a ribonucleoprotein complex containing also a RNA template molecule (TERC) and dyskerin. Exhaustion of telomeres during cell divisions triggers a DNA damage response that induces a senescence phenotype. The DNA damage machinery plays an essential role in maintaining the integrity of the genome and also detecting telomere shortening. However in some syndromes that involved mutations either in the telomerase complex genes or those involved in maintaining DNA secondary structure, such as the recQ helicase WRN, a higher frequency in the development of different types of malignancies is observed. We here describe the biology of some of these diseases, together with the molecular modifications in the telomerase complex genes and the impact of these alterations on the development of particular types of cancer.

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