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Blood Advances Sep 2022Patients with inborn errors of immunity (IEI) have a higher risk of developing cancer, especially lymphoma. However, the molecular basis for IEI-related lymphoma is...
Patients with inborn errors of immunity (IEI) have a higher risk of developing cancer, especially lymphoma. However, the molecular basis for IEI-related lymphoma is complex and remains elusive. Here, we perform an in-depth analysis of lymphoma genomes derived from 23 IEI patients. We identified and validated disease-causing or -associated germline mutations in 14 of 23 patients involving ATM, BACH2, BLM, CD70, G6PD, NBN, PIK3CD, PTEN, and TNFRSF13B. Furthermore, we profiled somatic mutations in the lymphoma genome and identified 8 genes that were mutated at a significantly higher level in IEI-associated diffuse large B-cell lymphomas (DLBCLs) than in non-IEI DLBCLs, such as BRCA2, NCOR1, KLF2, FAS, CCND3, and BRWD3. The latter, BRWD3, is furthermore preferentially mutated in tumors of a subgroup of activated phosphoinositide 3-kinase δ syndrome patients. We also identified 5 genomic mutational signatures, including 2 DNA repair deficiency-related signatures, in IEI-associated lymphomas and a strikingly high number of inter- and intrachromosomal structural variants in the tumor genome of a Bloom syndrome patient. In summary, our comprehensive genomic characterization of lymphomas derived from patients with rare genetic disorders expands our understanding of lymphomagenesis and provides new insights for targeted therapy.
Topics: Basic-Leucine Zipper Transcription Factors; Genomics; Humans; Lymphoma, Large B-Cell, Diffuse; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases
PubMed: 35687490
DOI: 10.1182/bloodadvances.2021006654 -
Frontiers in Cell and Developmental... 2021RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. These helicases play important roles in multiple cellular functions,... (Review)
Review
RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. These helicases play important roles in multiple cellular functions, including DNA replication, transcription, DNA repair, and telomere maintenance. Humans have five RecQ helicases: RECQL1, Bloom syndrome protein (BLM), Werner syndrome helicase (WRN), RECQL4, and RECQL5. Defects in BLM and WRN cause autosomal disorders: Bloom syndrome (BS) and Werner syndrome (WS), respectively. Mutations in RECQL4 are associated with three genetic disorders, Rothmund-Thomson syndrome (RTS), Baller-Gerold syndrome (BGS), and RAPADILINO syndrome. Although no genetic disorders have been reported due to loss of RECQL1 or RECQL5, dysfunction of either gene is associated with tumorigenesis. Multiple genetically independent pathways have evolved that mediate the repair of DNA double-strand break (DSB), and RecQ helicases play pivotal roles in each of them. The importance of DSB repair is supported by the observations that defective DSB repair can cause chromosomal aberrations, genomic instability, senescence, or cell death, which ultimately can lead to premature aging, neurodegeneration, or tumorigenesis. In this review, we will introduce the human RecQ helicase family, describe in detail their roles in DSB repair, and provide relevance between the dysfunction of RecQ helicases and human diseases.
PubMed: 33718381
DOI: 10.3389/fcell.2021.640755 -
Rheumatology and Immunology Research Dec 2023The gut microbiome represents a potential promising therapeutic target for autoimmune diseases. This review summarizes the current knowledge on the links between the gut...
The gut microbiome represents a potential promising therapeutic target for autoimmune diseases. This review summarizes the current knowledge on the links between the gut microbiome and several autoimmune rheumatic diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) spondyloarthropathies (SpA), Sjogren's syndrome (SS), and systemic sclerosis (SSc). Evidence from studies of RA and SLE patients suggests that alterations in the gut microbiome composition and function contribute to disease development and progression through increased gut permeability, with microbes and microbial metabolites driving an excessive systemic activation of the immune system. Also, there is growing evidence that gut dysbiosis and subsequent immune cell activation may contribute to disease pathogenesis in SpA and SS. For SSc, there are fewer, but these are still informative, reports on alterations in the gut microbiome. In general, the complex interplay between the microbiome and the immune system is still not fully understood. Here we discuss the current knowledge of the link between the gut microbiome and autoimmune rheumatic diseases, highlighting potentially fertile areas for future research and make considerations on the potential benefits of strategies that restore gut microbiome homeostasis.
PubMed: 38125641
DOI: 10.2478/rir-2023-0027 -
Mechanisms of Ageing and Development Jul 2018Progeroid syndrome is a group of disorders characterized by the early onset of diseases that are associated with aging. Best known examples are Werner syndrome, which is... (Review)
Review
Progeroid syndrome is a group of disorders characterized by the early onset of diseases that are associated with aging. Best known examples are Werner syndrome, which is adult onset and results from disease-causing DNA sequence variants in the RecQ helicase gene WRN, and Hutchison-Gilford progeria syndrome, which is childhood-onset and results from unique, recurrent disease-causing DNA sequence variants of the gene LMNA that encodes nuclear intermediate filaments. Related single gene RecQ disorders are Bloom syndrome and Rothmund-Thomson syndrome. The RecQ disorders Cockayne syndrome and xeroderma pigmentosum result from disease-causing DNA sequence variants in genes involved in the nucleotide excision repair pathway. RECQ2018: The International Meeting on RECQ Helicases and Related Diseases was held on February 16-18, 2018 in Chiba, Japan. The purpose of the meeting was to facilitate clinical and research collaborations for the goal of developing effective treatments for RECQ disorders and other progeroid syndromes.
Topics: Animals; Cockayne Syndrome; Congresses as Topic; DNA Repair; DNA Repair-Deficiency Disorders; Humans; Japan; Werner Syndrome Helicase
PubMed: 29752965
DOI: 10.1016/j.mad.2018.05.002 -
Structure (London, England : 1993) Feb 2021The Bloom syndrome complex is a DNA damage repair machine. It consists of several protein components which are functional in isolation, but interdependent in cells for... (Review)
Review
The Bloom syndrome complex is a DNA damage repair machine. It consists of several protein components which are functional in isolation, but interdependent in cells for the maintenance of accurate homologous recombination. Mutations to any of the genes encoding these proteins cause numerous physical and developmental markers as well as phenotypes of genome instability, infertility, and cancer predisposition. Here we review the published structural and biochemical data on each of the components of the complex: the helicase BLM, the type IA topoisomerase TOP3A, and the OB-fold-containing RMI and RPA subunits. We describe how each component contributes to function, interacts with each other, and the DNA that it manipulates/repairs.
Topics: Bloom Syndrome; DNA Topoisomerases, Type I; DNA-Binding Proteins; Homologous Recombination; Humans; RecQ Helicases
PubMed: 33357470
DOI: 10.1016/j.str.2020.11.020 -
Genes Dec 2018Accurate duplication and transmission of identical genetic information into offspring cells lies at the heart of a cell division cycle. During the last stage of cellular... (Review)
Review
Accurate duplication and transmission of identical genetic information into offspring cells lies at the heart of a cell division cycle. During the last stage of cellular division, namely mitosis, the fully replicated DNA molecules are condensed into X-shaped chromosomes, followed by a chromosome separation process called sister chromatid disjunction. This process allows for the equal partition of genetic material into two newly born daughter cells. However, emerging evidence has shown that faithful chromosome segregation is challenged by the presence of persistent DNA intertwining structures generated during DNA replication and repair, which manifest as so-called ultra-fine DNA bridges (UFBs) during anaphase. Undoubtedly, failure to disentangle DNA linkages poses a severe threat to mitosis and genome integrity. This review will summarize the possible causes of DNA bridges, particularly sister DNA inter-linkage structures, in an attempt to explain how they may be processed and how they influence faithful chromosome segregation and the maintenance of genome stability.
PubMed: 30545131
DOI: 10.3390/genes9120623 -
Ageing Research Reviews Jan 2017Genomic instability is a hallmark of cancer and aging. Premature aging (progeroid) syndromes are often caused by mutations in genes whose function is to ensure genomic... (Review)
Review
Genomic instability is a hallmark of cancer and aging. Premature aging (progeroid) syndromes are often caused by mutations in genes whose function is to ensure genomic integrity. The RecQ family of DNA helicases is highly conserved and plays crucial roles as genome caretakers. In humans, mutations in three RecQ genes - BLM, WRN, and RECQL4 - give rise to Bloom's syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS), respectively. WS is a prototypic premature aging disorder; however, the clinical features present in BS and RTS do not indicate accelerated aging. The BLM helicase has pivotal functions at the crossroads of DNA replication, recombination, and repair. BS cells exhibit a characteristic form of genomic instability that includes excessive homologous recombination. The excessive homologous recombination drives the development in BS of the many types of cancers that affect persons in the normal population. Replication delay and slower cell turnover rates have been proposed to explain many features of BS, such as short stature. More recently, aberrant transcriptional regulation of growth and survival genes has been proposed as a hypothesis to explain features of BS.
Topics: Aging; Aging, Premature; Bloom Syndrome; DNA Helicases; DNA Replication; Genomic Instability; Humans; Mutation; RecQ Helicases; Werner Syndrome; Werner Syndrome Helicase
PubMed: 27238185
DOI: 10.1016/j.arr.2016.05.010 -
EMBO Molecular Medicine May 2023Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the...
Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
Topics: Humans; Mitochondria; DNA, Mitochondrial; Mitochondrial Diseases; Muscular Diseases; Syndrome; Genomic Instability
PubMed: 37013609
DOI: 10.15252/emmm.202216775 -
Respirology (Carlton, Vic.) Jul 2023This review addresses some of the major lessons we have learnt regarding asthma and the covid-19 pandemic, including susceptibility to SARS-CoV-2 infection and severe... (Review)
Review
This review addresses some of the major lessons we have learnt regarding asthma and the covid-19 pandemic, including susceptibility to SARS-CoV-2 infection and severe covid-19, potentially protective factors, comparison to other respiratory infections, changes in healthcare behaviour from the perspective of patients and clinicians, medications to treat or prevent covid-19, and post-covid syndrome.
Topics: Humans; COVID-19; SARS-CoV-2; Pandemics; Asthma
PubMed: 37154075
DOI: 10.1111/resp.14515 -
Genetics in Medicine : Official Journal... Jul 2022This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these...
PURPOSE
This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these are not well-defined.
METHODS
Data from the Bloom Syndrome Registry (BSR) was used for this study. Cancer history, ages of first cancer diagnosis, and ages of death were compiled from the BSR and analyzed.
RESULTS
Among the 290 individuals in the BSR, 155 (53%) participants developed 251 malignant neoplasms; 100 (65%) were diagnosed with 1 malignancy, whereas the remaining 55 (35%) developed multiple malignancies. Of the 251 neoplasms, 83 (33%) were hematologic and 168 (67%) were solid tumors. Hematologic malignancies (leukemia and lymphoma) were more common than any of the solid tumors. The most commonly observed solid tumors were colorectal, breast, and oropharyngeal. The cumulative incidence of any malignancy by age 40 was 83%. The median survival for all participants in the BSR was 36.2 years. There were no significant differences in time to first cancer diagnosis or survival by genotype among the study participants.
CONCLUSION
We describe the spectrum of cancers observed in Bloom syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome. We also highlight the significant differences in survival and age of diagnosis seen among different tumor types and genotypes.
Topics: Adult; Bloom Syndrome; Hematologic Neoplasms; Humans; Incidence; Neoplasms; Registries
PubMed: 35420546
DOI: 10.1016/j.gim.2022.03.008