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Annals of the New York Academy of... Apr 2018The consequences of telomere dysfunction are most apparent in rare inherited syndromes caused by genetic deficiencies in factors that normally maintain telomeres. The... (Review)
Review
The consequences of telomere dysfunction are most apparent in rare inherited syndromes caused by genetic deficiencies in factors that normally maintain telomeres. The principal disease is known as dyskeratosis congenita (DC), but other syndromes with similar underlying genetic defects share some clinical aspects with this disease. Currently, there are no curative therapies for these diseases of telomere dysfunction. Here, we review recent findings demonstrating that dysfunctional (i.e., uncapped) telomeres can downregulate the WNT pathway, and that restoration of WNT signaling helps to recap telomeres by increasing expression of shelterins, proteins that naturally bind and protect telomeres. We discuss how these findings are different from previous observations connecting WNT and telomere biology, and discuss potential links between WNT and clinical manifestations of the DC spectrum of diseases. Finally, we argue for exploring the use of WNT agonists, specifically lithium, as a possible therapeutic approach for patients with DC.
Topics: Animals; Dyskeratosis Congenita; Humans; Telomere; Wnt Signaling Pathway
PubMed: 29722029
DOI: 10.1111/nyas.13692 -
Disease Models & Mechanisms Oct 2023p53 (encoded by Trp53) is a tumor suppressor, but mouse models have revealed that increased p53 activity may cause bone marrow failure, likely through dimerization...
p53 (encoded by Trp53) is a tumor suppressor, but mouse models have revealed that increased p53 activity may cause bone marrow failure, likely through dimerization partner, RB-like, E2F4/E2F5 and MuvB (DREAM) complex-mediated gene repression. Here, we designed a systematic approach to identify p53-DREAM pathway targets, the repression of which might contribute to abnormal hematopoiesis. We used Gene Ontology analysis to study transcriptomic changes associated with bone marrow cell differentiation, then chromatin immunoprecipitation-sequencing (ChIP-seq) data to identify DREAM-bound promoters. We next created positional frequency matrices to identify evolutionary conserved sequence elements potentially bound by DREAM. The same approach was developed to find p53-DREAM targets associated with brain abnormalities, also observed in mice with increased p53 activity. Putative DREAM-binding sites were found for 151 candidate target genes, of which 106 are mutated in a blood or brain genetic disorder. Twenty-one DREAM-binding sites were tested and found to impact gene expression in luciferase assays, to notably regulate genes mutated in dyskeratosis congenita (Rtel1), Fanconi anemia (Fanca), Diamond-Blackfan anemia (Tsr2), primary microcephaly [Casc5 (or Knl1), Ncaph and Wdr62] and pontocerebellar hypoplasia (Toe1). These results provide clues on the role of the p53-DREAM pathway in regulating hematopoiesis and brain development, with implications for tumorigenesis.
Topics: Animals; Mice; Brain; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p21; Promoter Regions, Genetic; Tumor Suppressor Protein p53
PubMed: 37661832
DOI: 10.1242/dmm.050376 -
RNA Biology Aug 2016The importance of telomere function for human health is exemplified by a collection of Mendelian disorders referred to as the telomere biology disorders (TBDs),... (Review)
Review
The importance of telomere function for human health is exemplified by a collection of Mendelian disorders referred to as the telomere biology disorders (TBDs), telomeropathies, or syndromes of telomere shortening. Collectively, the TBDs cover a spectrum of conditions from multisystem disease presenting in infancy to isolated disease presentations in adulthood, most notably idiopathic pulmonary fibrosis. Eleven genes have been found mutated in the TBDs to date, each of which is linked to some aspect of telomere maintenance. This review summarizes the molecular defects that result from mutations in these genes, highlighting recent advances, including the addition of PARN to the TBD gene family and the discovery of heterozygous mutations in RTEL1 as a cause of familial pulmonary fibrosis.
Topics: Animals; DNA Replication; Dyskeratosis Congenita; Enzyme Activation; Exoribonucleases; Genetic Association Studies; Genetic Predisposition to Disease; Genomic Instability; Humans; Mutation; Nucleic Acid Conformation; Protein Binding; Protein Transport; Syndrome; Telomerase; Telomere; Telomere Shortening
PubMed: 26400640
DOI: 10.1080/15476286.2015.1094596 -
Blood Nov 2017Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure,... (Review)
Review
Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with these syndromes age, as well as additional late effects following hematopoietic stem cell transplantation. The most common complications are iron overload in transfused patients and syndrome-specific malignancies in untransplanted patients, which may occur earlier and with higher risks in those who have received transplants.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Hematopoietic Stem Cell Transplantation; Hemoglobinuria, Paroxysmal; Humans; Inheritance Patterns
PubMed: 29167174
DOI: 10.1182/blood-2017-05-781799 -
Hematology. American Society of... Dec 2017Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure,... (Review)
Review
Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with these syndromes age, as well as additional late effects following hematopoietic stem cell transplantation. The most common complications are iron overload in transfused patients and syndrome-specific malignancies in untransplanted patients, which may occur earlier and with higher risks in those who have received transplants.
Topics: Allografts; Bone Marrow Diseases; Genetic Diseases, Inborn; Hematopoietic Stem Cell Transplantation; Humans; Syndrome
PubMed: 29222241
DOI: 10.1182/asheducation-2017.1.88 -
Biochemical Society Transactions Nov 2021Telomerase ribonucleoprotein was discovered over three decades ago as a specialized reverse transcriptase that adds telomeric repeats to the ends of linear eukaryotic... (Review)
Review
Telomerase ribonucleoprotein was discovered over three decades ago as a specialized reverse transcriptase that adds telomeric repeats to the ends of linear eukaryotic chromosomes. Telomerase plays key roles in maintaining genome stability; and its dysfunction and misregulation have been linked to different types of cancers and a spectrum of human genetic disorders. Over the years, a wealth of genetic and biochemical studies of human telomerase have illuminated its numerous fascinating features. Yet, structural studies of human telomerase have lagged behind due to various challenges. Recent technical developments in cryo-electron microscopy have allowed for the first detailed visualization of the human telomerase holoenzyme, revealing unprecedented insights into its active site and assembly. This review summarizes the cumulative work leading to the recent structural advances, as well as highlights how the future structural work will further advance our understanding of this enzyme.
Topics: Biocatalysis; Catalytic Domain; Cryoelectron Microscopy; Dyskeratosis Congenita; Holoenzymes; Humans; Models, Molecular; Mutation; Telomerase; Telomere; Telomere Homeostasis
PubMed: 34623385
DOI: 10.1042/BST20200042 -
American Journal of Human Genetics Aug 2022Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail...
Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail dystrophy, and oral leucoplakia. Despite the identification of several genetic variants that cause DC, a significant proportion of probands remain without a molecular diagnosis. In a cohort of eight independent DC-affected families, we have identified a remarkable series of heterozygous germline variants in the gene encoding thymidylate synthase (TYMS). Although the inheritance appeared to be autosomal recessive, one parent in each family had a wild-type TYMS coding sequence. Targeted genomic sequencing identified a specific haplotype and rare variants in the naturally occurring TYMS antisense regulator ENOSF1 (enolase super family 1) inherited from the other parent. Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1. These cell and molecular abnormalities generated by the combination of germline digenic variants at the TYMS-ENOSF1 locus represent a unique pathogenetic pathway for DC causation in these affected individuals, whereas the parents who are carriers of either of these variants in a singular fashion remain unaffected.
Topics: Dyskeratosis Congenita; Germ Cells; Heterozygote; Humans; Nucleotides; Thymidylate Synthase
PubMed: 35931051
DOI: 10.1016/j.ajhg.2022.06.014 -
Blood Mar 2019Myelodysplastic syndrome (MDS) typically presents in older adults with the acquisition of age-related somatic mutations, whereas MDS presenting in children and younger... (Review)
Review
Myelodysplastic syndrome (MDS) typically presents in older adults with the acquisition of age-related somatic mutations, whereas MDS presenting in children and younger adults is more frequently associated with germline genetic predisposition. Germline predisposition is increasingly recognized in MDS presenting at older ages as well. Although each individual genetic disorder is rare, as a group, the genetic MDS disorders account for a significant subset of MDS in children and young adults. Because many patients lack overt syndromic features, genetic testing plays an important role in the diagnostic evaluation. This review provides an overview of syndromes associated with genetic predisposition to MDS, discusses implications for clinical evaluation and management, and explores scientific insights gleaned from the study of MDS predisposition syndromes. The effects of germline genetic context on the selective pressures driving somatic clonal evolution are explored. Elucidation of the molecular and genetic pathways driving clonal evolution may inform surveillance and risk stratification, and may lead to the development of novel therapeutic strategies.
Topics: Adult; Aged; Anemia, Diamond-Blackfan; Bone Marrow Diseases; Child; Clonal Evolution; Dyskeratosis Congenita; Exocrine Pancreatic Insufficiency; Fanconi Anemia; GATA2 Transcription Factor; Genetic Association Studies; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Intracellular Signaling Peptides and Proteins; Li-Fraumeni Syndrome; Lipomatosis; Middle Aged; Myelodysplastic Syndromes; Proteins; Risk; Shwachman-Diamond Syndrome; Thrombocytopenia; Young Adult
PubMed: 30670445
DOI: 10.1182/blood-2018-10-844662 -
Human Pathology (New York) Sep 2021Dyskeratosis congenita is a disease of impaired tissue maintenance downstream of telomere dysfunction. Characteristically, patients present with the clinical triad of...
Dyskeratosis congenita is a disease of impaired tissue maintenance downstream of telomere dysfunction. Characteristically, patients present with the clinical triad of nail dystrophy, oral leukoplakia, and skin pigmentation defects, but the disease involves degenerative changes in multiple organs. Mutations in telomere-binding proteins such as TINF2 (TRF1-interacting nuclear factor 2) or in telomerase, the enzyme that counteracts age related telomere shortening, are causative in dyskeratosis congenita. We present a patient who presented with severe hypoxemia at age 13. The patient had a history of myelodysplastic syndrome treated with bone marrow transplant at the age of 5. At age 18 she was hospitalized for an acute pneumonia progressing to respiratory failure, developed renal failure and ultimately, she and her family opted to withdraw support as she was not a candidate for a lung transplant. Sequencing of the patient's TINF2 locus revealed a heterozygous mutation (c.844C > T, Arg282Cys) which has previously been reported in a subset of dyskeratosis congenita patients. Tissue sections from multiple organs showed degenerative changes including disorganized bone remodeling, diffuse alveolar damage and small vessel proliferation in the lung, and hyperkeratosis with hyperpigmentation of the skin. Autopsy samples revealed a bimodal distribution of telomere length, with telomeres from donor hematopoietic tissues being an age-appropriate length and those from patient tissues showing pathogenic shortening, with the shortest telomeres in lung, liver, and kidney. We report for the first time a survey of degenerative changes and telomere lengths in multiple organs in a patient with dyskeratosis congenita.
PubMed: 34522616
DOI: 10.1016/j.ehpc.2021.200517 -
Stem Cells (Dayton, Ohio) Sep 2020Telomeres are composed of repetitive DNA sequences that are replenished by the enzyme telomerase to maintain the self-renewal capacity of stem cells. The RNA component... (Review)
Review
Telomeres are composed of repetitive DNA sequences that are replenished by the enzyme telomerase to maintain the self-renewal capacity of stem cells. The RNA component of human telomerase (TERC) is the essential template for repeat addition by the telomerase reverse transcriptase (TERT), and also serves as a scaffold for several factors comprising the telomerase ribonucleoprotein (RNP). Unique features of TERC regulation and function have been informed not only through biochemical studies but also through human genetics. Disease-causing mutations impact TERC biogenesis at several levels including RNA transcription, post-transcriptional processing, folding, RNP assembly, and trafficking. Defects in TERC reduce telomerase activity and impair telomere maintenance, thereby causing a spectrum of degenerative diseases called telomere biology disorders (TBDs). Deciphering mechanisms of TERC dysregulation have led to a broader understanding of noncoding RNA biology, and more recently points to new therapeutic strategies for TBDs. In this review, we summarize over two decades of work revealing mechanisms of human telomerase RNA biogenesis, and how its disruption causes human diseases.
PubMed: 32875693
DOI: 10.1002/stem.3270