DOCSLIB.ORG

Diseases Associated with Defective Responses to DNA Damage

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Diseases Associated with Defective Responses to DNA Damage Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Diseases Associated with Defective Responses to DNA Damage Mark O’Driscoll Human DNA Damage Response Disorders Group Genome Damage and Stability Centre, University of Sussex, Brighton, East Sussex BN1 9RQ, United Kingdom Correspondence: [email protected] Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identi- fied, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways. he link between DNA damage, mutagenesis, sense XP represents a paradigm of a DNA repair Tand malignant transformation is long estab- disorder with a clear pathological link between lished. A logical extension is that a congenital genotype and phenotype (Cleaver et al. 2009). defect in a fundamental DNA repair pathway, As our knowledge of the complexity of ge- such as nucleotide excision repair (NER), would nome stability pathways has evolved, coupled be anticipated to be associated with a pro- with the explosive technical advances in molec- nounced cancer predisposition syndrome. In- ular and cellular biology, more and more hu- deed this is well known to be the case consid- man disorders caused by defects in components ering xeroderma pigmentosum (XP) (Cleaver that constitute the genome stability network 1968, 1969, 1970). In most XP subtypes, the continue to be described. At the most funda- devastatingly overt .1000-fold elevated risk of mental level, identification of these conditions developing basal and squamous cell carcinomas enables future accurate molecular diagnosis on sun-exposed areas of the skin is directly at- (Raffan et al. 2011). This has relevance for as- tributable to a failure to remove highly muta- sociated comorbidities and is vital for informed genic solar ultraviolet (UV) radiation-induced counseling of the parents, not just for family DNA photoproducts from the genome. In this planning and recurrence risk analysis, but can Editors: Errol C. Friedberg, Stephen J. Elledge, Alan R. Lehmann, Tomas Lindahl, and Marco Muzi-Falconi Additional Perspectives on DNA Repair, Mutagenesis, and Other Responses to DNA Damage available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a012773 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a012773 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press M. O’Driscoll assuage destructive feelings of maternal/pater- examples of some of the novel disorders that nal guilt and bring to an end what is often a have been described since 2005. I will first re- protracted and extremely stressful journey to view disorders of DNA repair pathways, includ- ascertain a clinical diagnosis (Raymond et al. ing those of nonhomologous DNA end joining 2010; Evans et al. 2011; Baker et al. 2012). These (NHEJ), base excision repair (BER)–single- disorders can also help inform the biology of strand break repair (SSBR), NER, and homolo- genome stability. Their diverse and often unan- gous recombination (HR)–interstrand cross- ticipated clinical features can provide evidence link (ICL) repair, before highlighting disorders for previously unappreciated biological connec- associated with defects in the DNA damage-in- tions (Griffith et al. 2008; Rauch et al. 2008; duced signal transduction responses (phos- Huang-Doran et al. 2011). Furthermore, these phorylation and ubiquitination). insights can help optimize therapeutic strate- gies for these conditions along with more com- NOVEL DISORDERS OF NHEJ mon conditions such as cancer. For example, the application of nonmyeloablative condition- The mechanics of the NHEJ pathway are out- ing protocols for bone marrow transplantation lined in Chiruvella et al. (2013). Two disorders, to combat the severe anemia and lymphoid ma- one caused by deficiency of a novel component, lignancy in Fanconi anemia, or the use of re- the other by mutation of a well-known compo- duced intensity radiotherapy strategies to treat nent ofNHEJ,havebeendescribed recently.Cells lymphoma in ataxia telangiectasia patients have from both disorders show pronounced defects both been developed directly from our under- in DNA double-strand break repair (DSBR). standing the inherent sensitivity of cells from these patients to specific forms of DNA damage Cernunnos/XLF-SCID (Gennery et al. 2005; Resnick et al. 2005; Lavin 2008). The interest in developing specific inhib- NHEJ represents an important means of direct- itors toward “drug-able” targets that play key ly repairing DNA double-strand breaks (DSBs) roles in DNA repair and the DNA damage re- by a resealing process not dependent on the sponse, to increase the selective sensitivity of availability of a homologous DNA strand. One tumor cells toward conventional DNA-damag- of the primary functions of NHEJ is the repair of ing therapies such as radiotherapy and certain programmed DSBs in the immunoglobin (Ig) chemotherapies is currently an active area of and T-cell receptor (TCR) gene loci during the interest (Bryant and Helleday 2004; Helleday process of V(D)J recombination to form the et al. 2008; Evers et al. 2010; Helleday 2010). complete Ig and TCR repertoire of the immune Since 2005, there have been several nota- system (Lieber 2010). Indeed the known human ble descriptions of novel congenital disorders conditions defective in a core component of caused by defects in known, or more important- NHEJ, DNA ligase IV (LIG4) causing LIG4 syn- ly, novel components of several DNA repair and drome and Artemis (DCLRE1C) causing Art- DNA damage response pathways. These condi- SCID (severe combined immunodeficiency), tions have been identified via a combination of are associated with pronounced T- and B-cell approaches: candidate gene approaches coupled deficiencies (Moshous et al. 2001; O’Driscoll to educated guesswork based on known biolo- et al. 2001, 2004; O’Driscoll and Jeggo 2006). gy of a particular pathway; by classical homo- These patients suffer frequent infections from zygosity linkage analysis using consanguineous an early age, invariably presenting initially in families; and in recent years, by the growing the immunology clinic. Because of the DSB re- influence of next-generation whole exome se- pair defect and consequent ionizing radiation quencing. The latter approach, in particular, of- sensitivity of cells from these patients, these fers the tantalizing prospect of being able to conditions are denoted as radiosensitive (RS)- identify additional potential genetic defects us- SCID, distinguishing them from other more ing single affected patients. Here, I will review common causes of SCID such as RAG1/2or 2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a012773 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Diseases and Defective Responses to DNA Damage adenosine deaminase deficiency (Riballo et al. cleavage at the Ig and TCR loci. Failure to pro- 2004). cess these coding ends effectively results in SCID Understanding the cellularand clinical spec- (Moshous et al. 2001; Ma et al. 2002). trum of RS-SCID enabled the subsequent iden- Compound heterozygous mutations in tification of defects in what transpired to be a PRKDC, the gene encoding DNA-PKcs, were novel NHEJ component: Cernunnos/XRCC4- recently identified in a single case of RS-SCID like factor (XLF), caused by mutations in without associated developmental features such NHEJ1. Using a functional cDNA library-based as the microcephaly and growth delay seen complementation cloning strategy, Buck and in LIG4 syndrome and Cernunnos/XLF-SCID colleagues used fibroblasts from a series of pa- (van der Burg et al. 2009a,b). It is noteworthy in tients characterized by pronounced T- and B- this context that Artemis deficiency similarly is cell-minus SCID, growth retardation, and mi- not associated with developmental abnormali- crocephaly (phenotypes reminiscent of LIG4 ties (Moshous et al. 2001; Li et al. 2002). The syndrome), identifying multiple mutations in identification of this novel and long-predicted a novel gene they called Cernunnos (Buck et al. genetic defect (spontaneous DNA-PKcs defects 2006). In a complementary approach, Ahnesorg occur in Jack Russell terrier dogs, Arabian and colleagues showed that a previously unde- horses, and mice [Fig. 1]) is owing to a thorough scribed XRCC4 interactant they had identified analysis of the immunological profile of the af- (XLF; XRCC4-like factor) was defective in a fected case (Bosma et al. 1983; Peterson et al. well-characterized
Load more

Recommended publications
  • Identification of the DNA Repair Defects in a Case of Dubowitz Syndrome
    Identification of the DNA Repair Defects in a Case of Dubowitz Syndrome Jingyin Yue, Huimei Lu, Shijie Lan, Jingmei Liu, Mark N. Stein, Bruce G. Haffty, Zhiyuan Shen* The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America Abstract Dubowitz Syndrome is an autosomal recessive disorder with a unique set of clinical features including microcephaly and susceptibility to tumor formation. Although more than 140 cases of Dubowitz syndrome have been reported since 1965, the genetic defects of this disease has not been identified. In this study, we systematically analyzed the DNA damage response and repair capability of fibroblasts established from a Dubowitz Syndrome patient. Dubowitz syndrome fibroblasts are hypersensitive to ionizing radiation, bleomycin, and doxorubicin. However, they have relatively normal sensitivities to mitomycin-C, cisplatin, and camptothecin. Dubowitz syndrome fibroblasts also have normal DNA damage signaling and cell cycle checkpoint activations after DNA damage. These data implicate a defect in repair of DNA double strand break (DSB) likely due to defective non-homologous end joining (NHEJ). We further sequenced several genes involved in NHEJ, and identified a pair of novel compound mutations in the DNA Ligase IV gene. Furthermore, expression of wild type DNA ligase IV completely complement the DNA repair defects in Dubowitz syndrome fibroblasts, suggesting that the DNA ligase IV mutation is solely responsible for the DNA repair defects. These data suggests that at least subset of Dubowitz syndrome can be attributed to DNA ligase IV mutations. Citation: Yue J, Lu H, Lan S, Liu J, Stein MN, et al.
    [Show full text]
  • Open Full Page
    CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders Michael F. Walsh1, Vivian Y. Chang2, Wendy K. Kohlmann3, Hamish S. Scott4, Christopher Cunniff5, Franck Bourdeaut6, Jan J. Molenaar7, Christopher C. Porter8, John T. Sandlund9, Sharon E. Plon10, Lisa L. Wang10, and Sharon A. Savage11 Abstract DNA repair syndromes are heterogeneous disorders caused by around the world to discuss and develop cancer surveillance pathogenic variants in genes encoding proteins key in DNA guidelines for children with cancer-prone disorders. Herein, replication and/or the cellular response to DNA damage. The we focus on the more common of the rare DNA repair dis- majority of these syndromes are inherited in an autosomal- orders: ataxia telangiectasia, Bloom syndrome, Fanconi ane- recessive manner, but autosomal-dominant and X-linked reces- mia, dyskeratosis congenita, Nijmegen breakage syndrome, sive disorders also exist. The clinical features of patients with DNA Rothmund–Thomson syndrome, and Xeroderma pigmento- repair syndromes are highly varied and dependent on the under- sum. Dedicated syndrome registries and a combination of lying genetic cause. Notably, all patients have elevated risks of basic science and clinical research have led to important in- syndrome-associated cancers, and many of these cancers present sights into the underlying biology of these disorders. Given the in childhood. Although it is clear that the risk of cancer is rarity of these disorders, it is recommended that centralized increased, there are limited data defining the true incidence of centers of excellence be involved directly or through consulta- cancer and almost no evidence-based approaches to cancer tion in caring for patients with heritable DNA repair syn- surveillance in patients with DNA repair disorders.
    [Show full text]
  • Download The
    PROBING THE INTERACTION OF ASPERGILLUS FUMIGATUS CONIDIA AND HUMAN AIRWAY EPITHELIAL CELLS BY TRANSCRIPTIONAL PROFILING IN BOTH SPECIES by POL GOMEZ B.Sc., The University of British Columbia, 2002 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2010 © Pol Gomez, 2010 ABSTRACT The cells of the airway epithelium play critical roles in host defense to inhaled irritants, and in asthma pathogenesis. These cells are constantly exposed to environmental factors, including the conidia of the ubiquitous mould Aspergillus fumigatus, which are small enough to reach the alveoli. A. fumigatus is associated with a spectrum of diseases ranging from asthma and allergic bronchopulmonary aspergillosis to aspergilloma and invasive aspergillosis. Airway epithelial cells have been shown to internalize A. fumigatus conidia in vitro, but the implications of this process for pathogenesis remain unclear. We have developed a cell culture model for this interaction using the human bronchial epithelium cell line 16HBE and a transgenic A. fumigatus strain expressing green fluorescent protein (GFP). Immunofluorescent staining and nystatin protection assays indicated that cells internalized upwards of 50% of bound conidia. Using fluorescence-activated cell sorting (FACS), cells directly interacting with conidia and cells not associated with any conidia were sorted into separate samples, with an overall accuracy of 75%. Genome-wide transcriptional profiling using microarrays revealed significant responses of 16HBE cells and conidia to each other. Significant changes in gene expression were identified between cells and conidia incubated alone versus together, as well as between GFP positive and negative sorted cells.
    [Show full text]
  • FANCJ Regulates the Stability of FANCD2/FANCI Proteins and Protects Them from Proteasome and Caspase-3 Dependent Degradation
    FANCJ regulates the stability of FANCD2/FANCI proteins and protects them from proteasome and caspase-3 dependent degradation Komaraiah Palle, Ph.D. (Kumar) Assistant Professor of Oncologic Sciences Abraham Mitchell Cancer Research Scholar Mitchell Cancer Institute University of South Alabama Outline • Fanconi anemia (FA) pathway • Role of FA pathway in Genome maintenance • FANCJ and FANCD2 functional relationship • FANCJ-mediated DDR in response to Fork-stalling Fanconi Anemia • Rare, inherited blood disorder. • 1:130,000 births Guido Fanconi 1892-1979 • Affects men and women equally. • Affects all racial and ethnic groups – higher incidence in Ashkenazi Jews and Afrikaners Birth Defects Fanconi anemia pathway • FA is a rare chromosome instability syndrome • Autosomal recessive disorder (or X-linked) • Developmental abnormalities • 17 complementation groups identified to date • FA pathway is involved in DNA repair • Increased cancer susceptibility - many patients develop AML - in adults solid tumors Fanconi Anemia is an aplastic anemia FA patients are prone to multiple types of solid tumors • Increased incidence and earlier onset cancers: oral cavity, GI and genital and reproductive tract head and neck breast esophagus skin liver brain Why? FA is a DNA repair disorder • FA caused by mutations in 17 genes: FANCA FANCF FANCM FANCB FANCG/XRCC9 FANCN/PALB2 FANCC FANCI RAD51C/FANCO FANCD1/BRCA2 FANCJ SLX4/FANCP FANCD2 FANCL ERCC2/XPF/FANCQ FANCE BRCA1/FANCS • FA genes function in DNA repair processes • FA patient cells are highly sensitive
    [Show full text]
  • DNA Damage Response and Cancer Therapeutics Through the Lens of the Fanconi Anemia DNA Repair Pathway Sonali Bhattacharjee* and Saikat Nandi*
    Bhattacharjee and Nandi Cell Communication and Signaling (2017) 15:41 DOI 10.1186/s12964-017-0195-9 REVIEW Open Access DNA damage response and cancer therapeutics through the lens of the Fanconi Anemia DNA repair pathway Sonali Bhattacharjee* and Saikat Nandi* Abstract Fanconi Anemia (FA) is a rare, inherited genomic instability disorder, caused by mutations in genes involved in the repair of interstrand DNA crosslinks (ICLs). The FA signaling network contains a unique nuclear protein complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. FA proteins act at different steps of ICL repair in sensing, recognition and processing of DNA lesions. The multi-protein network is tightly regulated by complex mechanisms, such as ubiquitination, phosphorylation, and degradation signals that are critical for the maintenance of genome integrity and suppressing tumorigenesis. Here, we discuss recent advances in our understanding of how the FA proteins participate in ICL repair and regulation of the FA signaling network that assures the safeguard of the genome. We further discuss the potential application of designing small molecule inhibitors that inhibit the FA pathway and are synthetic lethal with DNA repair enzymes that can be used for cancer therapeutics. Keywords: DNA repair, Fanconi Anemia (FA) signaling network, DNA damage response, Cancer therapeutics, Synthetic lethality, Combination Therapy Genomic instability, Interstrand crosslink (ICL), Homologous recombination, Translesion synthesis Background Additional clinical features included microcephaly, vitiligo Fanconi Anemia (FA), a rare genetic cancer-susceptibility and hypoplasia of the testes [8]. After nearly four decades syndrome is a recessive autosomal or X-linked genetic dis- another article reported an accumulation of large number ease [1–3].
    [Show full text]
  • DNA Ligase IV Syndrome; a Review Thomas Altmann1 and Andrew R
    Altmann and Gennery Orphanet Journal of Rare Diseases (2016) 11:137 DOI 10.1186/s13023-016-0520-1 REVIEW Open Access DNA ligase IV syndrome; a review Thomas Altmann1 and Andrew R. Gennery1,2* Abstract DNA ligase IV deficiency is a rare primary immunodeficiency, LIG4 syndrome, often associated with other systemic features. DNA ligase IV is part of the non-homologous end joining mechanism, required to repair DNA double stranded breaks. Ubiquitously expressed, it is required to prevent mutagenesis and apoptosis, which can result from DNA double strand breakage caused by intracellular events such as DNA replication and meiosis or extracellular events including damage by reactive oxygen species and ionising radiation. Within developing lymphocytes, DNA ligase IV is required to repair programmed DNA double stranded breaks induced during lymphocyte receptor development. Patients with hypomorphic mutations in LIG4 present with a range of phenotypes, from normal to severe combined immunodeficiency. All, however, manifest sensitivity to ionising radiation. Commonly associated features include primordial growth failure with severe microcephaly and a spectrum of learning difficulties, marrow hypoplasia and a predisposition to lymphoid malignancy. Diagnostic investigations include immunophenotyping, and testing for radiosensitivity. Some patients present with microcephaly as a predominant feature, but seemingly normal immunity. Treatment is mainly supportive, although haematopoietic stem cell transplantation has been used in a few cases. Keywords: DNA Ligase 4, Severe combined immunodeficiency, Primordial dwarfism, Radiosensitive, Lymphoid malignancy Background factors include intracellular events such as DNA replica- DNA ligase IV deficiency (OMIM 606593) or LIG4 syn- tion and meiosis, and extracellular events including drome (ORPHA99812), also known as Ligase 4 syn- damage by reactive oxygen species and ionising radi- drome, is a rare autosomal recessive disorder ation.
    [Show full text]
  • Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients
    cancers Article Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients Jesús del Valle 1,2,3 , Paula Rofes 1,2,3 , José Marcos Moreno-Cabrera 1,2,3 , Adriana López-Dóriga 4,5, Sami Belhadj 1,2,3 , Gardenia Vargas-Parra 1,2,3, Àlex Teulé 1,2,6, Raquel Cuesta 1,2,3, Xavier Muñoz 1,2,3, Olga Campos 1,2,3,Mónica Salinas 1,2, Rafael de Cid 7, Joan Brunet 1,2,3, Sara González 1,2,3, Gabriel Capellá 1,2,3 , Marta Pineda 1,2,3 , Lídia Feliubadaló 1,2,3 and Conxi Lázaro 1,2,3,* 1 Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL-IGTP-IDIBGI, 08908 Hospitalet de Llobregat, Spain; [email protected] (J.d.V.); [email protected] (P.R.); [email protected] (J.M.M.-C.); [email protected] (S.B.); [email protected] (G.V.-P.); [email protected] (À.T.); [email protected] (R.C.); [email protected] (X.M.); [email protected] (O.C.); [email protected] (M.S.); [email protected] (J.B.); [email protected] (S.G.); [email protected] (G.C.); [email protected] (M.P.); [email protected] (L.F.) 2 Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, 08908 Hospitalet de Llobregat, Spain 3 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain 4 Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology, 08908 Hospitalet de Llobregat, Spain; [email protected] 5 Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain 6 Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, 08908 Hospitalet de Llobregat, Spain 7 Genomes for Life—GCAT lab Group, Institut Germans Trias i Pujol (IGTP), 08916 Badalona, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-93-2607145 Received: 7 February 2020; Accepted: 25 March 2020; Published: 30 March 2020 Abstract: Fanconi anemia (FA) is caused by biallelic mutations in FA genes.
    [Show full text]
  • MECHANISMS in ENDOCRINOLOGY: Novel Genetic Causes of Short Stature
    J M Wit and others Genetics of short stature 174:4 R145–R173 Review MECHANISMS IN ENDOCRINOLOGY Novel genetic causes of short stature 1 1 2 2 Jan M Wit , Wilma Oostdijk , Monique Losekoot , Hermine A van Duyvenvoorde , Correspondence Claudia A L Ruivenkamp2 and Sarina G Kant2 should be addressed to J M Wit Departments of 1Paediatrics and 2Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Email The Netherlands [email protected] Abstract The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature.
    [Show full text]
  • Epigenetic Regulation of DNA Repair Genes and Implications for Tumor Therapy ⁎ ⁎ Markus Christmann , Bernd Kaina
    Mutation Research-Reviews in Mutation Research xxx (xxxx) xxx–xxx Contents lists available at ScienceDirect Mutation Research-Reviews in Mutation Research journal homepage: www.elsevier.com/locate/mutrev Review Epigenetic regulation of DNA repair genes and implications for tumor therapy ⁎ ⁎ Markus Christmann , Bernd Kaina Department of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany ARTICLE INFO ABSTRACT Keywords: DNA repair represents the first barrier against genotoxic stress causing metabolic changes, inflammation and DNA repair cancer. Besides its role in preventing cancer, DNA repair needs also to be considered during cancer treatment Genotoxic stress with radiation and DNA damaging drugs as it impacts therapy outcome. The DNA repair capacity is mainly Epigenetic silencing governed by the expression level of repair genes. Alterations in the expression of repair genes can occur due to tumor formation mutations in their coding or promoter region, changes in the expression of transcription factors activating or Cancer therapy repressing these genes, and/or epigenetic factors changing histone modifications and CpG promoter methylation MGMT Promoter methylation or demethylation levels. In this review we provide an overview on the epigenetic regulation of DNA repair genes. GADD45 We summarize the mechanisms underlying CpG methylation and demethylation, with de novo methyl- TET transferases and DNA repair involved in gain and loss of CpG methylation, respectively. We discuss the role of p53 components of the DNA damage response, p53, PARP-1 and GADD45a on the regulation of the DNA (cytosine-5)- methyltransferase DNMT1, the key enzyme responsible for gene silencing. We stress the relevance of epigenetic silencing of DNA repair genes for tumor formation and tumor therapy.
    [Show full text]
  • Genomic Analysis of Bone Marrow Failure and Myelodysplastic Syndromes Reveals Phenotypic and Diagnostic Complexity
    ARTICLES Bone Marrow Failure Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity Michael Y. Zhang, 1 Siobán B. Keel, 2 Tom Walsh, 3 Ming K. Lee, 3 Suleyman Gulsuner, 3 Amanda C. Watts, 3 Colin C. Pritchard, 4 Stephen J. Salipante, 4 Michael R. Jeng, 5 Inga Hofmann, 6 David A. Williams, 6,7 Mark D. Fleming, 8 Janis L. Abkowitz, 2 Mary-Claire King, 3 and Akiko Shimamura 1,9,10 M.Y.Z. and S.B.K. contributed equally to this work. 1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 2Department of Medicine, Division of Hematology, University of Washington, Seattle, WA; 3Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA; 4Department of Laboratory Medicine, University of Washington, Seattle, WA; 5Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; 6Division of Hematology/Oncology, Boston Children’s Hospital, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA; 7Harvard Stem Cell Institute, Boston, MA; 8Department of Pathology, Boston Children’s Hospital, MA; 9Department of Pediatric Hematology/Oncology, Seattle Children’s Hospital, WA; 10 Department of Pediatrics, University of Washington, Seattle, WA, USA ABSTRACT Accurate and timely diagnosis of inherited bone marrow failure and inherited myelodysplastic syndromes is essen - tial 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.
    [Show full text]
  • Blueprint Genetics Comprehensive Skeletal Dysplasias and Disorders
    Comprehensive Skeletal Dysplasias and Disorders Panel Test code: MA3301 Is a 251 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of disorders involving the skeletal system. About Comprehensive Skeletal Dysplasias and Disorders This panel covers a broad spectrum of skeletal disorders including common and rare skeletal dysplasias (eg. achondroplasia, COL2A1 related dysplasias, diastrophic dysplasia, various types of spondylo-metaphyseal dysplasias), various ciliopathies with skeletal involvement (eg. short rib-polydactylies, asphyxiating thoracic dysplasia dysplasias and Ellis-van Creveld syndrome), various subtypes of osteogenesis imperfecta, campomelic dysplasia, slender bone dysplasias, dysplasias with multiple joint dislocations, chondrodysplasia punctata group of disorders, neonatal osteosclerotic dysplasias, osteopetrosis and related disorders, abnormal mineralization group of disorders (eg hypopohosphatasia), osteolysis group of disorders, disorders with disorganized development of skeletal components, overgrowth syndromes with skeletal involvement, craniosynostosis syndromes, dysostoses with predominant craniofacial involvement, dysostoses with predominant vertebral involvement, patellar dysostoses, brachydactylies, some disorders with limb hypoplasia-reduction defects, ectrodactyly with and without other manifestations, polydactyly-syndactyly-triphalangism group of disorders, and disorders with defects in joint formation and synostoses. Availability 4 weeks Gene Set Description
    [Show full text]
  • Clinical and Immunological Diversity of Recombination Defects Hanna
    Clinical and Immunological Diversity Defects of Recombination Hanna IJspeert Clinical and immunological diversity of recombination defects Hanna IJspeert 2014 Clinical and Immunological Diversity of Recombination Defects Hanna IJspeert The research for this thesis was performed within the framework of the Erasmus Postgraduate School Molecular Medicine. The studies described in the thesis were performed at the Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands and collaborating institutions. The studies were financially suported by ‘Sophia Kinderziekhuis Fonds’ (grant 589). The printing of this thesis was supported by Erasmus MC, Stichting Kind & Afweer, CSL Behring and BD Biosciences. ISBN: 978-94-91811-04-3 Illustrations: Sandra de Bruin-Versteeg, Hanna IJspeert Cover: Stephanie van Brandwijk Lay-out: Caroline Linker Printing: Haveka B.V., Alblasserdam, the Netherlands Copyright © 2014 by Hanna IJspeert. All rights reserved. No part of this book may be reproduced, stored in a retrieval system of transmitted in any form or by any means, without prior permission of the author. Clinical and Immunological Diversity of Recombination Defects Klinische en immunologische diversiteit van recombinatie defecten Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.A.P. Pols en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 19 maart 2014 om 13.30 uur door Hanna IJspeert geboren te Dordrecht PROMOTIE COMMISSIE Promotoren Prof.dr. J.J.M. van Dongen Prof.dr. A.J. van der Heijden Overige leden Prof.dr. B.H. Gaspar Prof.dr. F.J.T. Staal Dr.
    [Show full text]