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Mayo Clinic Proceedings Jul 2020With the advent of precision genomics, hereditary predisposition to hematopoietic neoplasms- collectively known as hereditary predisposition syndromes (HPS)-are being... (Review)
Review
With the advent of precision genomics, hereditary predisposition to hematopoietic neoplasms- collectively known as hereditary predisposition syndromes (HPS)-are being increasingly recognized in clinical practice. Familial clustering was first observed in patients with leukemia, which led to the identification of several germline variants, such as RUNX1, CEBPA, GATA2, ANKRD26, DDX41, and ETV6, among others, now established as HPS, with tendency to develop myeloid neoplasms. However, evidence for hereditary predisposition is also apparent in lymphoid and plasma--cell neoplasms, with recent discoveries of germline variants in genes such as IKZF1, SH2B3, PAX5 (familial acute lymphoblastic leukemia), and KDM1A/LSD1 (familial multiple myeloma). Specific inherited bone marrow failure syndromes-such as GATA2 haploinsufficiency syndromes, short telomere syndromes, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, severe congenital neutropenia, and familial thrombocytopenias-also have an increased predisposition to develop myeloid neoplasms, whereas inherited immune deficiency syndromes, such as ataxia-telangiectasia, Bloom syndrome, Wiskott Aldrich syndrome, and Bruton agammaglobulinemia, are associated with an increased risk for lymphoid neoplasms. Timely recognition of HPS is critical to ensure safe choice of donors and/or conditioning-regimen intensity for allogeneic hematopoietic stem-cell transplantation and to enable direction of appropriate genomics-driven personalized therapies. The purpose of this review is to provide a comprehensive overview of HPS and serve as a useful reference for clinicians to recognize relevant signs and symptoms among patients to enable timely screening and referrals to pursue germline assessment. In addition, we also discuss our institutional approach toward identification of HPS and offer a stepwise diagnostic and management algorithm.
Topics: Genetic Predisposition to Disease; Germ-Line Mutation; Hematologic Neoplasms; Humans; Neoplastic Syndromes, Hereditary; Precision Medicine
PubMed: 32571604
DOI: 10.1016/j.mayocp.2019.12.013 -
Molecular Cell May 2024The Bloom syndrome (BLM) helicase is critical for alternative lengthening of telomeres (ALT), a homology-directed repair (HDR)-mediated telomere maintenance mechanism...
The Bloom syndrome (BLM) helicase is critical for alternative lengthening of telomeres (ALT), a homology-directed repair (HDR)-mediated telomere maintenance mechanism that is prevalent in cancers of mesenchymal origin. The DNA substrates that BLM engages to direct telomere recombination during ALT remain unknown. Here, we determine that BLM helicase acts on lagging strand telomere intermediates that occur specifically in ALT-positive cells to assemble a replication-associated DNA damage response. Loss of ATRX was permissive for BLM localization to ALT telomeres in S and G2, commensurate with the appearance of telomere C-strand-specific single-stranded DNA (ssDNA). DNA2 nuclease deficiency increased 5'-flap formation in a BLM-dependent manner, while telomere C-strand, but not G-strand, nicks promoted ALT. These findings define the seminal events in the ALT DNA damage response, linking aberrant telomeric lagging strand DNA replication with a BLM-directed HDR mechanism that sustains telomere length in a subset of human cancers.
Topics: RecQ Helicases; Humans; Telomere Homeostasis; Telomere; DNA Replication; DNA Damage; DNA, Single-Stranded; X-linked Nuclear Protein; DNA Helicases; Bloom Syndrome; Cell Line, Tumor
PubMed: 38593805
DOI: 10.1016/j.molcel.2024.03.011 -
Genomics, Proteomics & Bioinformatics Jun 2016DNA double-strand breaks (DSBs), which arise following exposure to a number of endogenous and exogenous agents, can be repaired by either the homologous recombination... (Review)
Review
DNA double-strand breaks (DSBs), which arise following exposure to a number of endogenous and exogenous agents, can be repaired by either the homologous recombination (HR) or non-homologous end-joining (NHEJ) pathways in eukaryotic cells. A vital step in HR repair is DNA end resection, which generates a long 3' single-stranded DNA (ssDNA) tail that can invade the homologous DNA strand. The generation of 3' ssDNA is not only essential for HR repair, but also promotes activation of the ataxia telangiectasia and Rad3-related protein (ATR). Multiple factors, including the MRN/X complex, C-terminal-binding protein interacting protein (CtIP)/Sae2, exonuclease 1 (EXO1), Bloom syndrome protein (BLM)/Sgs1, DNA2 nuclease/helicase, and several chromatin remodelers, cooperate to complete the process of end resection. Here we review the basic machinery involved in DNA end resection in eukaryotic cells.
Topics: Chromatin Assembly and Disassembly; DNA; DNA Breaks, Double-Stranded; DNA Repair; Exodeoxyribonucleases; Genomic Instability; Homologous Recombination; Humans; RecQ Helicases
PubMed: 27240470
DOI: 10.1016/j.gpb.2016.05.002 -
European Journal of Medical Genetics Nov 2020Aging is a physiological process that is in part genetically determined. Some of the signs and symptoms of aging also occur prematurely in Mendelian disorders. Such... (Review)
Review
Aging is a physiological process that is in part genetically determined. Some of the signs and symptoms of aging also occur prematurely in Mendelian disorders. Such disorders are excellent sources of information of underlying mechanisms for these components of aging, and studying these may allow detection of pathways that have not yet considered in detail in physiological aging. Here I define the clinical characteristics that constitute aging and propose that at least 40% of aging signs and symptoms should be present before an entity should be tagged as progeroid. A literature search using these characteristics yields 17 entities that fulfill this definition: Hutchinson-Gilford progeria, mandibulo-acral dysplasia, Nestor-Guillermo progeria, Werner syndrome, Cockayne syndrome, cutis laxa progeroid, Penttinen progeroid syndrome, Mandibular underdevelopment, Deafness, Progeroid features, Lipodystrophy, Fontaine progeroid syndrome, SHORT syndrome, Wiedemann-Rautenstrauch syndrome, Mulvihill-Smith syndrome, dyskeratosis congenita, Marfan syndrome lipodystrophy type, Warburg-Cinotti syndrome, Lessel syndrome and Bloom syndrome. The presenting and main characteristics of these entities are indicated briefly. Their pathophysiology is not complete pathophysiology is reviewed but only the pathophysiology of the premature aging characteristics of this series of entities is compared to the known mechanisms ("Hallmarks") of physiological aging as summarized in the review paper by Lopez-Otin and colleagues. Although many causative genes have not been studied fully for all known aging mechanisms the comparison demonstrates that additional mechanisms must play a role to explain the aging characteristic in some of the progeroid entities of the progeroid entities, and possibly also in physiological aging.
Topics: Aging; Genetic Heterogeneity; Humans; Phenotype; Progeria
PubMed: 32791128
DOI: 10.1016/j.ejmg.2020.104028 -
Clinical Cancer Research : An Official... Jun 2017DNA repair syndromes are heterogeneous disorders caused by pathogenic variants in genes encoding proteins key in DNA replication and/or the cellular response to DNA... (Review)
Review
DNA repair syndromes are heterogeneous disorders caused by pathogenic variants in genes encoding proteins key in DNA replication and/or the cellular response to DNA damage. The majority of these syndromes are inherited in an autosomal-recessive manner, but autosomal-dominant and X-linked recessive disorders also exist. The clinical features of patients with DNA repair syndromes are highly varied and dependent on the underlying genetic cause. Notably, all patients have elevated risks of syndrome-associated cancers, and many of these cancers present in childhood. Although it is clear that the risk of cancer is increased, there are limited data defining the true incidence of cancer and almost no evidence-based approaches to cancer surveillance in patients with DNA repair disorders. This article is the product of the October 2016 AACR Childhood Cancer Predisposition Workshop, which brought together experts from around the world to discuss and develop cancer surveillance guidelines for children with cancer-prone disorders. Herein, we focus on the more common of the rare DNA repair disorders: ataxia telangiectasia, Bloom syndrome, Fanconi anemia, dyskeratosis congenita, Nijmegen breakage syndrome, Rothmund-Thomson syndrome, and Xeroderma pigmentosum. Dedicated syndrome registries and a combination of basic science and clinical research have led to important insights into the underlying biology of these disorders. Given the rarity of these disorders, it is recommended that centralized centers of excellence be involved directly or through consultation in caring for patients with heritable DNA repair syndromes.
Topics: Ataxia Telangiectasia; Bloom Syndrome; Child; DNA Repair; DNA Repair-Deficiency Disorders; Early Detection of Cancer; Fanconi Anemia; Humans; Neoplasms; Xeroderma Pigmentosum
PubMed: 28572264
DOI: 10.1158/1078-0432.CCR-17-0465 -
Cell Death & Disease Apr 2022RecQ helicases-also known as the "guardians of the genome"-play crucial roles in genome integrity maintenance through their involvement in various DNA metabolic...
RecQ helicases-also known as the "guardians of the genome"-play crucial roles in genome integrity maintenance through their involvement in various DNA metabolic pathways. Aside from being conserved from bacteria to vertebrates, their importance is also reflected in the fact that in humans impaired function of multiple RecQ helicase orthologs are known to cause severe sets of problems, including Bloom, Werner, or Rothmund-Thomson syndromes. Our aim was to create and characterize a zebrafish (Danio rerio) disease model for Bloom syndrome, a recessive autosomal disorder. In humans, this syndrome is characterized by short stature, skin rashes, reduced fertility, increased risk of carcinogenesis, and shortened life expectancy brought on by genomic instability. We show that zebrafish blm mutants recapitulate major hallmarks of the human disease, such as shortened lifespan and reduced fertility. Moreover, similarly to other factors involved in DNA repair, some functions of zebrafish Blm bear additional importance in germ line development, and consequently in sex differentiation. Unlike fanc genes and rad51, however, blm appears to affect its function independent of tp53. Therefore, our model will be a valuable tool for further understanding the developmental and molecular attributes of this rare disease, along with providing novel insights into the role of genome maintenance proteins in somatic DNA repair and fertility.
Topics: Animals; Bloom Syndrome; Germ Cells; Longevity; RecQ Helicases; Zebrafish
PubMed: 35436990
DOI: 10.1038/s41419-022-04815-8 -
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 -
Annals of Surgical Oncology Jun 2022
Editorial Comment to "High Expression of Bloom Syndrome Helicase is a Key Factor for Poor Prognosis and Advanced Malignancy in Patients with Pancreatic Cancer: A Retrospective Study".
Topics: Bloom Syndrome; Humans; Pancreatic Neoplasms; Prognosis; Retrospective Studies
PubMed: 35312901
DOI: 10.1245/s10434-022-11587-0 -
Neurobiology of Disease May 2023RecQ helicase family proteins play vital roles in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five...
RecQ helicase family proteins play vital roles in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five RecQ helicases: RECQL1, Bloom syndrome (BLM), Werner syndrome (WRN), RECQL4, and RECQL5. Dysfunction or absence of RecQ proteins is associated with genetic disorders, tumorigenesis, premature aging, and neurodegeneration. The biochemical and biological roles of RecQ helicases are rather well established, however, there is no systematic study comparing the behavioral changes among various RecQ-deficient mice including consequences of exposure to DNA damage. Here, we investigated the effects of ionizing irradiation (IR) on three RecQ-deficient mouse models (RecQ1, WRN and RecQ4). We find abnormal cognitive behavior in RecQ-deficient mice in the absence of IR. Interestingly, RecQ dysfunction impairs social ability and induces depressive-like behavior in mice after a single exposure to IR, suggesting that RecQ proteins play roles in mood and cognition behavior. Further, transcriptomic and metabolomic analyses revealed significant alterations in RecQ-deficient mice, especially after IR exposure. In particular, pathways related to neuronal and microglial functions, DNA damage repair, cell cycle, and reactive oxygen responses were downregulated in the RecQ4 and WRN mice. In addition, increased DNA damage responses were found in RecQ-deficient mice. Notably, two genes, Aldolase Fructose-Bisphosphate B (Aldob) and NADPH Oxidase 4 (Nox4), were differentially expressed in RecQ-deficient mice. Our findings suggest that RecQ dysfunction contributes to social and depressive-like behaviors in mice, and that aldolase activity may be associated with these changes, representing a potential therapeutic target.
Topics: Animals; Humans; Mice; RecQ Helicases; DNA Replication; DNA Repair; DNA Damage; Genomic Instability; Aldehyde-Lyases
PubMed: 36948261
DOI: 10.1016/j.nbd.2023.106092 -
Trends in Biochemical Sciences Sep 2014Holliday junctions (HJs) are four-stranded DNA intermediates that arise during the recombinational repair of DNA double-strand breaks (DSBs). Their timely removal is... (Review)
Review
Holliday junctions (HJs) are four-stranded DNA intermediates that arise during the recombinational repair of DNA double-strand breaks (DSBs). Their timely removal is crucial for faithful chromosome segregation and genome stability. In mammalian cells, HJs are processed by the BTR (BLM-topoisomerase IIIα-RMI1-RMI2) complex, the SLX-MUS (SLX1-SLX4-MUS81-EME1) complex, and the GEN1 resolvase. Recent studies have linked the deficiency of one or more of these enzymes to perturbed DNA replication, impaired crosslink repair, chromosomal instability, and defective mitoses, coupled with the transmission of widespread DNA damage and high levels of mortality. We review these key advances and how they have cemented the status of HJ-processing enzymes as guardians of genome integrity and viability in mammalian cells.
Topics: Animals; DNA Damage; DNA Replication; DNA, Cruciform; Genomic Instability; Holliday Junction Resolvases; Humans; Recombination, Genetic
PubMed: 25131815
DOI: 10.1016/j.tibs.2014.07.003