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GeroScience Aug 2023Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure....
Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null (Tert) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.
Topics: Humans; Animals; Mice; NAD; Telomere; Dyskeratosis Congenita; Inflammation; Hematopoietic Stem Cell Transplantation
PubMed: 36826621
DOI: 10.1007/s11357-023-00752-2 -
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 -
Cureus Nov 2023Background Oral submucous fibrosis (OSMF) is a chronic, progressive, and potentially malignant oral disorder that causes scarring of the oral cavity, pharynx, and...
Background Oral submucous fibrosis (OSMF) is a chronic, progressive, and potentially malignant oral disorder that causes scarring of the oral cavity, pharynx, and upper oesophagus. It is most common in Southeast Asia, but it is also found in other parts of the world. Oral potentially malignant disorders (OPMDs) are a group of oral lesions that have an increased risk of developing into oral cancer. The study aimed to evaluate the prevalence of OSMF associated with other OPMDs. The presence of multiple OPMDs existing in one patient is a significant finding, as it is associated with an elevated risk of developing malignancy. The risk of malignant transformation increases with the number of OPMDs present in a patient; patients with two OPMDs have a three to four times higher risk of developing malignancy than those with a single OPMD. Patients with three or more OPMDs have a 7-10 times higher risk and the risk of malignant transformation depends on the type of OPMD. Materials and methods The study was conducted in the Department of Oral Medicine and Radiology, Saveetha Dental College and Hospitals, Chennai, India, to investigate the prevalence of OSMF with other OPMDs. The study team retrieved 630 case records of patients with OSMF from the electronic database between January 2018 and March 2023. All of the patients in the study had OSMF, as well as other OPMDs such as leukoplakia, candidiasis, actinic cheilitis, dyskeratosis congenita, erythroplakia, lichen planus, sideropenic dysphagia (Plummer-Vinson syndrome), and discoid lupus erythematosus. Both clinical and histopathological examinations confirmed these diagnoses. Oral mucosal lesions without coexisting OSMF were excluded. The study was done on the basis of age group, habits, type of habits, associated coexisting lesions, and systemic condition. Results The patients were clinically examined and diagnosed. Of the 630 cases, 10% had OSMF with OPMDs. The most common OPMDs associated with OSMF were leukoplakia (86%), followed by candidiasis (12%) and both leukoplakia and candidiasis (2%). Based on gender, the incidence of OSMF was higher in males compared to females with 67% and 33%, respectively. Conclusion OSMF is more likely to develop into malignancy; the widespread use of areca nut products in India has contributed to the rising incidence of OSMF. Accumulating epidemiological data can help to identify high-risk populations for prevention and control measures. Earlier oral cancer diagnosis and treatment can increase the likelihood of a favourable outcome.
PubMed: 38161840
DOI: 10.7759/cureus.49642 -
Oxford Medical Case Reports May 2024Dyskeratosis congenita (DKC) is a rare genetic disorder characterized by lacy reticular skin hyperpigmentation, bone marrow failure, nail dystrophy, and oral...
Dyskeratosis congenita (DKC) is a rare genetic disorder characterized by lacy reticular skin hyperpigmentation, bone marrow failure, nail dystrophy, and oral leukoplakia. To the best of our knowledge, only around 200 cases were reported in the medical literature, and in this report, we present another distinctive case from Syria. This case report describes a male patient with generalized reticular pigmentation and abnormal nails since childhood. The patient reported a history of recurrent urethral stenosis and corneal density. Dermoscopic examination revealed pigmented lines arranged in a netlike pattern. Histopathological findings were nonspecific. Hematological values were unremarkable. A contrast CT scan revealed changes in the bladder wall. The final diagnosis of Dyskeratosis Congenita was made based on the clinical criteria. This disorder can present with additional cutaneous manifestations and systemic complications. Treatment are generally prescribed to maintain bone marrow function, based on the fact that it is the major cause of death. Regular monitoring and screening for associated conditions are recommended.
PubMed: 38784779
DOI: 10.1093/omcr/omae049 -
G3 (Bethesda, Md.) Nov 2023Aging is the consequence of intra- and extracellular events that promote cellular senescence. Dyskeratosis congenita (DC) is an example of a premature aging disorder...
Aging is the consequence of intra- and extracellular events that promote cellular senescence. Dyskeratosis congenita (DC) is an example of a premature aging disorder caused by underlying telomere/telomerase-related mutations. Cells from these patients offer an opportunity to study telomere-related aging and senescence. Our previous work has found that telomere shortening stimulates DNA damage responses (DDRs) and increases reactive oxygen species (ROS), thereby promoting entry into senescence. This work also found that telomere elongation via TERT expression, the catalytic component of the telomere-elongating enzyme telomerase, or p53 shRNA could decrease ROS by disrupting this telomere-DDR-ROS pathway. To further characterize this pathway, we performed a CRISPR/Cas9 knockout screen to identify genes that extend life span in DC cells. Of the cellular clones isolated due to increased life span, 34% had a guide RNA (gRNA) targeting CEBPB, while gRNAs targeting WSB1, MED28, and p73 were observed multiple times. CEBPB is a transcription factor associated with activation of proinflammatory response genes suggesting that inflammation may be present in DC cells. The inflammatory response was investigated using RNA sequencing to compare DC and control cells. Expression of inflammatory genes was found to be significantly elevated (P < 0.0001) in addition to a key subset of these inflammation-related genes [IL1B, IL6, IL8, IL12A, CXCL1 (GROa), CXCL2 (GROb), and CXCL5]. which are regulated by CEBPB. Exogenous TERT expression led to downregulation of RNA/protein CEBPB expression and the inflammatory response genes suggesting a telomere length-dependent mechanism to regulate CEBPB. Furthermore, unlike exogenous TERT and p53 shRNA, CEBPB shRNA did not significantly decrease ROS suggesting that CEBPB's contribution in DC cells' senescence is ROS independent. Our findings demonstrate a key role for CEBPB in engaging senescence by mobilizing an inflammatory response within DC cells.
Topics: Humans; Reactive Oxygen Species; Dyskeratosis Congenita; Telomerase; Tumor Suppressor Protein p53; Mutation; Telomere; RNA, Small Interfering; Fibroblasts; Inflammation; Mediator Complex; CCAAT-Enhancer-Binding Protein-beta
PubMed: 37717172
DOI: 10.1093/g3journal/jkad207 -
The Journal of Biological Chemistry Sep 2023The levels of non-coding RNAs (ncRNAs) are regulated by transcription, RNA processing, and RNA degradation pathways. One mechanism for the degradation of ncRNAs involves... (Review)
Review
The levels of non-coding RNAs (ncRNAs) are regulated by transcription, RNA processing, and RNA degradation pathways. One mechanism for the degradation of ncRNAs involves the addition of oligo(A) tails by non-canonical poly(A) polymerases, which then recruit processive sequence-independent 3' to 5' exonucleases for RNA degradation. This pathway of decay is also regulated by three 3' to 5' exoribonucleases, USB1, PARN, and TOE1, which remove oligo(A) tails and thereby can protect ncRNAs from decay in a manner analogous to the deubiquitination of proteins. Loss-of-function mutations in these genes lead to premature degradation of some ncRNAs and lead to specific human diseases such as Poikiloderma with Neutropenia (PN) for USB1, Dyskeratosis Congenita (DC) for PARN and Pontocerebellar Hypoplasia type 7 (PCH7) for TOE1. Herein, we review the biochemical properties of USB1, PARN, and TOE1, how they modulate ncRNA levels, and their roles in human diseases.
Topics: Humans; Dyskeratosis Congenita; Exoribonucleases; Neutropenia; RNA Stability; RNA, Untranslated; Loss of Function Mutation
PubMed: 37544646
DOI: 10.1016/j.jbc.2023.105139 -
Hereditas Dec 2023Dyskeratosis congenita 1 (DKC1), a critical component of telomerase complex, is highly expressed in a variety of human cancers. However, the association of DKC1 with...
BACKGROUND
Dyskeratosis congenita 1 (DKC1), a critical component of telomerase complex, is highly expressed in a variety of human cancers. However, the association of DKC1 with cancer occurrence and development stages is not clear, making a pan-cancer analysis crucial.
METHODS
We conducted a study using various bioinformatic databases such as TIMER, GEPIA, UALCAN, and KM plotter Analysis to examine the different expressions of DKC1 in multiple tissues and its correlation with pathological stages. Through KEGG analysis, GO enrichment analysis and Venn analysis, we were able to reveal DKC1-associated genes and signaling pathways. In addition, we performed several tests including the CCK, wound healing assay, cell cycle arrest assay, transwell assay and Sa-β-gal staining on DKC1-deleted MDA-231 cells.
RESULTS
Our study demonstrates that DKC1 has relatively low expression specificity in different tissues. Furthermore, we found that in ACC, KICH, KIRP and LIHC, the expression level of DKC1 is positively correlated with pathological stages. Conversely, in NHSC, KIRP, LGG, LIHC, MESO and SARC, we observed a negative influence of DKC1 expression level on the overall survival rate. We also found a significant positive correlation between DKC1 expression and Tumor Mutational Burden in 14 tumors. Additionally, we observed a significantly negative impact of DKC1 DNA methylation on gene expression at the promoter region in BRCA. We also identified numerous phosphorylation sites concentrated at the C-terminus of the DKC1 protein. Our GO analysis revealed a correlation between DKC1 and ribosomal biosynthesis pathways, and the common element UTP14A was identified. We also observed decreased rates of cell proliferation, migration and invasion abilities in DKC1-knockout MDA-MB-231 cell lines. Furthermore, DKC1-knockout induced cell cycle arrest and caused cell senescence.
CONCLUSIONS
Our findings suggest that the precise expression of DKC1 is closely associated with the occurrence and developmental stages of cancer in multiple tissues. Depletion of DKC1 can inhibit the abilities of cancer cells to proliferate, migrate, and invade by arresting the cell cycle and inducing cell senescence. Therefore, DKC1 may be a valuable prognostic biomarker for the diagnosis and treatment of cancer in various tissues.
Topics: Humans; Prognosis; Cell Cycle Proteins; Dyskeratosis Congenita; Neoplasms; Biomarkers; Nuclear Proteins
PubMed: 38082360
DOI: 10.1186/s41065-023-00302-y -
Frontiers in Pediatrics 2023Dyskeratosis congenita (DC) is a multisystem and ultra-rare hereditary disease characterized by somatic involvement, bone marrow failure, and predisposition to cancer....
BACKGROUND
Dyskeratosis congenita (DC) is a multisystem and ultra-rare hereditary disease characterized by somatic involvement, bone marrow failure, and predisposition to cancer. The main objective of this study is to describe the natural history of DC through a cohort of patients diagnosed in childhood and followed up for a long period of time.
MATERIAL AND METHODS
Multicenter, retrospective, longitudinal study conducted in patients followed up to 24 years since being diagnosed in childhood (between 1998 and 2020).
RESULTS
Fourteen patients were diagnosed with DC between the ages of 3 and 17 years (median, 8.5 years). They all had hematologic manifestations at diagnosis, and nine developed mucocutaneous manifestations during the first decade of life. Seven presented severe DC variants. All developed non-hematologic manifestations during follow-up. Mutations were identified in 12 patients. Thirteen progressed to bone marrow failure at a median age of 8 years [range, 3-18 years], and eight received a hematopoietic stem cell transplant. Median follow-up time was 9 years [range, 2-24 years]. Six patients died, the median age was 13 years [range, 6-24 years]. As of November 2022, eight patients were still alive, with a median age of 18 years [range, 6-32 years]. None of them have developed myeloblastic syndrome or cancer.
CONCLUSIONS
DC was associated with high morbidity and mortality in our series. Hematologic manifestations appeared early and consistently. Non-hematologic manifestations developed progressively. No patient developed cancer possibly due to their young age. Due to the complexity of the disease multidisciplinary follow-up and adequate transition to adult care are essential.
PubMed: 37593443
DOI: 10.3389/fped.2023.1182476 -
Genes Sep 2023The highly conserved family of cyclophilins comprises multifunctional chaperones that interact with proteins and RNAs, facilitating the dynamic assembly of...
The highly conserved family of cyclophilins comprises multifunctional chaperones that interact with proteins and RNAs, facilitating the dynamic assembly of multimolecular complexes involved in various cellular processes. Cyclophilin A (CypA), the predominant member of this family, exhibits peptidyl-prolyl cis-trans isomerase activity. This enzymatic function aids with the folding and activation of protein structures and often serves as a molecular regulatory switch for large multimolecular complexes, ensuring appropriate inter- and intra-molecular interactions. Here, we investigated the involvement of CypA in the nucleus, where it plays a crucial role in supporting the assembly and trafficking of heterogeneous ribonucleoproteins (RNPs). We reveal that CypA is enriched in the nucleolus, where it colocalizes with the pseudouridine synthase dyskerin, the catalytic component of the multifunctional H/ACA RNPs involved in the modification of cellular RNAs and telomere stability. We show that dyskerin, whose mutations cause the X-linked dyskeratosis (X-DC) and the Hoyeraal-Hreidarsson congenital ribosomopathies, can directly interact with CypA. These findings, together with the remark that substitution of four dyskerin prolines are known to cause X-DC pathogenic mutations, lead us to indicate this protein as a CypA client. The data presented here suggest that this chaperone can modulate dyskerin activity influencing all its partecipated RNPs.
Topics: Humans; Catalysis; Cyclophilin A; Dyskeratosis Congenita; Ribonucleoproteins; RNA-Binding Proteins
PubMed: 37761906
DOI: 10.3390/genes14091766 -
Leukemia Jun 2024Recent advances in in-depth data-independent acquisition proteomic analysis have enabled comprehensive quantitative analysis of >10,000 proteins. Herein, an integrated...
Recent advances in in-depth data-independent acquisition proteomic analysis have enabled comprehensive quantitative analysis of >10,000 proteins. Herein, an integrated proteogenomic analysis for inherited bone marrow failure syndrome (IBMFS) was performed to reveal their biological features and to develop a proteomic-based diagnostic assay in the discovery cohort; dyskeratosis congenita (n = 12), Fanconi anemia (n = 11), Diamond-Blackfan anemia (DBA, n = 9), Shwachman-Diamond syndrome (SDS, n = 6), ADH5/ALDH2 deficiency (n = 4), and other IBMFS (n = 18). Unsupervised proteomic clustering identified eight independent clusters (C1-C8), with the ribosomal pathway specifically downregulated in C1 and C2, enriched for DBA and SDS, respectively. Six patients with SDS had significantly decreased SBDS protein expression, with two of these not diagnosed by DNA sequencing alone. Four patients with ADH5/ALDH2 deficiency showed significantly reduced ADH5 protein expression. To perform a large-scale rapid IBMFS screening, targeted proteomic analysis was performed on 417 samples from patients with IBMFS-related hematological disorders (n = 390) and healthy controls (n = 27). SBDS and ADH5 protein expressions were significantly reduced in SDS and ADH5/ALDH2 deficiency, respectively. The clinical application of this first integrated proteogenomic analysis would be useful for the diagnosis and screening of IBMFS, where appropriate clinical screening tests are lacking.
Topics: Humans; Bone Marrow Failure Disorders; Proteogenomics; Male; Female; Bone Marrow Diseases; Child; Adult; Adolescent; Child, Preschool; Anemia, Diamond-Blackfan; Young Adult; Fanconi Anemia; Proteomics; Infant; Shwachman-Diamond Syndrome; Dyskeratosis Congenita
PubMed: 38740980
DOI: 10.1038/s41375-024-02263-1