DOCSLIB.ORG

Robin Paul, Jeffrey P. Solzak, Milan Radovich Indiana University School of Medicine, Indianapolis, Indiana

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Robin Paul, Jeffrey P. Solzak, Milan Radovich Indiana University School of Medicine, Indianapolis, Indiana Whole genome sequencing analysis of 77 breast cancer patients reveal increased germline transposable element insertions responsible for early onset of cancer Robin Paul, Jeffrey P. Solzak, Milan Radovich Indiana University School of Medicine, Indianapolis, Indiana Comparison of germline TE insertions Abstract TE insertion analysis on 77 TCGA breast cancer patients against age of diagnosis More than 50% of the human genome consists of transposable Moderate germline and somatic TE correlation L1 most active type of TE in somatic TE insertions High germline TE patients tend to have a lower age elements (TE), which mostly remain inactive and relatively of diagnosis (high TE: 47yrs, low TE = 59.77yrs) stable in healthy individuals. However, some retrotransposons P=0.019 are believed to become active during cancer due to loss of epigenetic silencing and DNA damage repair mechanisms. In this study, we analyzed somatic and germline TE insertions in 77 TCGA breast cancer (BC) cases and performed association analysis with corresponding somatic and germline variants. In our analysis, we identified a subset of patients who harbored a high number of germline TE insertions. Statistical burden testing of germline TE insertions with germline genetic variants (SNPs and Indels), revealed an enrichment of deleterious variants in the FANCF, MLH1, LGR6 and RING1 genes. These genes are known to regulate TEs using RNA silencing and other DNA damage repair mechanisms. Further, patients with Fig. 5 - Box plot of top 25% and bottom 75% germline TE patient’s age of high germline TE insertions had a lower median age of diagnosis of breast cancer (Welch’s two sample t-test p-value = 0.019, median diagnosis (top quartile vs bottom 75%, p-value=0.019), age of high TE patients = 47.15yrs, median age of low TE patients = 59.77yrs) suggesting a potential novel role of TEs in cancer predisposition. Lastly, comparison of somatic TE insertion Germline variant analysis pattern against somatic tumor mutation burden revealed an Fig. 3(a) Scatter plot of whole genome somatic TEs vs whole genome germline TEs (b) Scatter plot of ratio of (somatic L1)/(total somatic TE) vs total somatic TE mutually exclusive relationship, indicating that analysis of TE (Pearson correlation coefficient, R2 = 0.61, p-value = 4.84 × 10-9) insertions is critical to breast cancer diagnosis in the clinic. No enrichment of germline TEs between No enrichment of somatic TEs between Fig. 6 – Bioinformatics various hormonal status various hormonal status pipeline for variant analysis Bioinformatics Methodology of TCGA breast cancer patients Results of gene burden analysis Table 1 – List of (a) Germline (b) Somatic mutations in genes (and their corresponding biological pathway) responsible for silencing TEs (a) Germline variant analysis vs germline TEs gene-burden analysis Fig. 1 - Bioinformatics methodology for determination of TE inserts from LGR6, FANCF – Known TE repressor whole genome sequencing (WGS) data. MLH1, MSH6 - DNA repair TNRC6B - Epigenetic silencing (b) Germline + somatic variant analysis vs germline + somatic TEs gene-burden analysis Wet-lab validation in HCC1143 cell line (c) Somatic and (d) germline TE distribution in whole genomes of 77 TCGA breast cancer patients subdivided by histological type (TNBC, HER2+ and ER/PR+). MLH1, MSH6 - DNA repair TNRC6B, RING1 - Epigenetic regulation CCNK - transcriptional regulation Comparison of somatic TE insertions trend against tumor mutation burden LGR6, FANCF, ZNF10 – Known TE repressor and microsatellite instability Discussion We explore TE insertion as another type of mutation which may be Somatic TEs and TMB are mutually exclusive Somatic TEs and MSI are mutually exclusive responsible for cancer. Designed a bioinformatics pipeline (Fig. 1) for determination of TE insertions from WGS data and validated on the HCC1143 cell line (Fig. 2). High germline TE insertion patients tend to also have high somatic TE patients (Fig. 3a). L1 and ALU are the most active type of germline TEs Fig. 2 (a) View of PBRM1 gene (b) Gel electrophoresis of PCR whereas in case of somatic TEs L1s seem to be only active type of TE locus harboring TE insertion. amplified PBRM1 gene locus (Fig. 3b). TE insertions not specific towards any specific hormonal status (Fig. 3c and 3d). Comparison of somatic TEs against tumor mutation burden (TMB) (Fig. 500bp Tumor 4a) and microsatellite instability (MI) (Fig. 4b) reveals an mutually line exclusive relationship suggesting analysis of TE insertions is necessary 400bp to get the complete mutation profile of a patient. 300bp Blood On comparing germline TEs against age of diagnosis reveals top quartile 200bp line of higher germline TE patients having lower age of diagnosis than other patients suggesting TEs could be responsible for cancer predisposition Tumor Blood (Fig. 5). (c) Gel electrophoresis of PCR (d) Sanger sequencing of PCR (b) Scatterplot of number of whole genome somatic TE insertions vs Variant analysis (Fig. 6) revealed several deleterious germline and Fig. 4 (a) Scatterplot of number of whole genome somatic TE insertions somatic mutations in genes known to be responsible for silencing TEs amplified TMEM181 gene amplified TMEM181 gene locus vs total mutation burden (from COSMIC database). total microsatellite instability. locus (Table 1).
Load more

Recommended publications
  • Structure and Function of the Human Recq DNA Helicases
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2005 Structure and function of the human RecQ DNA helicases Garcia, P L Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-34420 Dissertation Published Version Originally published at: Garcia, P L. Structure and function of the human RecQ DNA helicases. 2005, University of Zurich, Faculty of Science. Structure and Function of the Human RecQ DNA Helicases Dissertation zur Erlangung der naturwissenschaftlichen Doktorw¨urde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultat¨ der Universitat¨ Z ¨urich von Patrick L. Garcia aus Unterseen BE Promotionskomitee Prof. Dr. Josef Jiricny (Vorsitz) Prof. Dr. Ulrich H ¨ubscher Dr. Pavel Janscak (Leitung der Dissertation) Z ¨urich, 2005 For my parents ii Summary The RecQ DNA helicases are highly conserved from bacteria to man and are required for the maintenance of genomic stability. All unicellular organisms contain a single RecQ helicase, whereas the number of RecQ homologues in higher organisms can vary. Mu- tations in the genes encoding three of the five human members of the RecQ family give rise to autosomal recessive disorders called Bloom syndrome, Werner syndrome and Rothmund-Thomson syndrome. These diseases manifest commonly with genomic in- stability and a high predisposition to cancer. However, the genetic alterations vary as well as the types of tumours in these syndromes. Furthermore, distinct clinical features are observed, like short stature and immunodeficiency in Bloom syndrome patients or premature ageing in Werner Syndrome patients. Also, the biochemical features of the human RecQ-like DNA helicases are diverse, pointing to different roles in the mainte- nance of genomic stability.
    [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]
  • Fanconi Anemia, Bloom Syndrome and Breast Cancer
    A multiprotein complex in DNA damage response network of Fanconi anemia, Bloom syndrome and Breast cancer Weidong Wang Lab of Genetics, NIA A Multi-protein Complex Connects Two Genomic Instability Diseases: Bloom Syndrome and Fanconi Anemia Bloom Syndrome . Genomic Instability: -sister-chromatid exchange . Cancer predisposition . Mutation in BLM, a RecQ DNA Helicase . BLM participates in: HR-dependent DSB repair Recovery of stalled replication forks . BLM works with Topo IIIa and RMI to Suppress crossover recombination Courtesy of Dr. Ian Hickson A Multi-protein Complex Connects Two Genomic Instability Diseases: Bloom Syndrome and Fanconi Anemia P I l o r t n o BLM IP kDa C HeLa BLAP 250 Nuclear Extract 200- BLM* FANCA* 116- TOPO IIIα* 97- BLAP 100 MLH1* BLM IP BLAP 75 * 66- RPA 70 IgG H 45- * 30- RPA32 IgG L 20- * 12- RPA14 Meetei et al. MCB 2003 A Multi-protein Complex Connects Two Genomic Instability Diseases: Bloom Syndrome and Fanconi Anemia P I A C N A F BLM IP HeLa FANCM= FAAP 250 BLAP 250 Nuclear Extract BLM* BLM* * FANCA* FANCA TOPO IIIα* TOPO IIIα* FAAP 100 BLAP 100 FANCB= FAAP 95 MLH1 FANCA IP BLM IP BLAP 75 BLAP 75 RPA70*/FANCG* RPA 70* FANCC*/FANCE* IgG H FANCL= FAAP 43 FANCF* RPA32* IgG L Meetei et al. MCB 2003 Meetei et al. Nat Genet. 2003, 2004, 2005 BRAFT-a Multisubunit Machine that Maintains Genome Stability and is defective in Fanconi anemia and Bloom syndrome BRAFT Super-complex Fanconi Anemia Bloom Syndrome Core Complex Complex 12 polypeptides 7 polypeptides FANCA BLM Helicase (HJ, fork, D-loop), fork FANCC regression, dHJ dissolution Topo IIIα Topoisomerase, FANCE dHJ dissolution FANCF BLAP75 RMI1 FANCG Stimulates dHJ dissolution.
    [Show full text]
  • HEREDITARY CANCER PANELS Part I
    Pathology and Laboratory Medicine Clinic Building, K6, Core Lab, E-655 2799 W. Grand Blvd. HEREDITARY CANCER PANELS Detroit, MI 48202 855.916.4DNA (4362) Part I- REQUISITION Required Patient Information Ordering Physician Information Name: _________________________________________________ Gender: M F Name: _____________________________________________________________ MRN: _________________________ DOB: _______MM / _______DD / _______YYYY Address: ___________________________________________________________ ICD10 Code(s): _________________/_________________/_________________ City: _______________________________ State: ________ Zip: __________ ICD-10 Codes are required for billing. When ordering tests for which reimbursement will be sought, order only those tests that are medically necessary for the diagnosis and treatment of the patient. Phone: _________________________ Fax: ___________________________ Billing & Collection Information NPI: _____________________________________ Patient Demographic/Billing/Insurance Form is required to be submitted with this form. Most genetic testing requires insurance prior authorization. Due to high insurance deductibles and member policy benefits, patients may elect to self-pay. Call for more information (855.916.4362) Bill Client or Institution Client Name: ______________________________________________________ Client Code/Number: _____________ Bill Insurance Prior authorization or reference number: __________________________________________ Patient Self-Pay Call for pricing and payment options Toll
    [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]
  • Insights Into MYC Biology Through Investigation of Synthetic Lethal Interactions with MYC Deregulation
    Insights into MYC biology through investigation of synthetic lethal interactions with MYC deregulation Mai Sato Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Mai Sato All Rights Reserved ABSTRACT Insights into MYC biology through investigation of synthetic lethal interactions with MYC deregulation Mai Sato MYC (or c-myc) is a bona fide “cancer driver” oncogene that is deregulated in up to 70% of human tumors. In addition to its well-characterized role as a transcription factor that can directly promote tumorigenic growth and proliferation, MYC has transcription-independent functions in vital cellular processes including DNA replication and protein synthesis, contributing to its complex biology. MYC expression, activity, and stability are highly regulated through multiple mechanisms. MYC deregulation triggers genome instability and oncogene-induced DNA replication stress, which are thought to be critical in promoting cancer via mechanisms that are still unclear. Because regulated MYC activity is essential for normal cell viability and MYC is a difficult protein to target pharmacologically, targeting genes or pathways that are essential to survive MYC deregulation offer an attractive alternative as a means to combat tumor cells with MYC deregulation. To this end, we conducted a genome-wide synthetic lethal shRNA screen in MCF10A breast epithelial cells stably expressing an inducible MYCER transgene. We identified and validated FBXW7 as a high-confidence synthetic lethal (MYC-SL) candidate gene. FBXW7 is a component of an E3 ubiquitin ligase complex that degrades MYC. FBXW7 knockdown in MCF10A cells selectively induced cell death in MYC-deregulated cells compared to control.
    [Show full text]
  • Bloom Syndrome Complex Promotes FANCM Recruitment to Stalled Replication Forks and Facilitates Both Repair and Traverse of DNA Interstrand Crosslinks
    OPEN Citation: Cell Discovery (2016) 2, 16047; doi:10.1038/celldisc.2016.47 ARTICLE www.nature.com/celldisc Bloom syndrome complex promotes FANCM recruitment to stalled replication forks and facilitates both repair and traverse of DNA interstrand crosslinks Chen Ling1, Jing Huang2,4, Zhijiang Yan1, Yongjiang Li1, Mioko Ohzeki3, Masamichi Ishiai3, Dongyi Xu1,5, Minoru Takata3, Michael Seidman2, Weidong Wang1 1Lab of Genetics, National Institute on Aging, National Institute of Health, Baltimore, MD, USA; 2Lab of Molecular Gerontology, National Institute on Aging, National Institute of Health, Baltimore, MD, USA; 3Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan The recruitment of FANCM, a conserved DNA translocase and key component of several DNA repair protein complexes, to replication forks stalled by DNA interstrand crosslinks (ICLs) is a step upstream of the Fanconi anemia (FA) repair and replication traverse pathways of ICLs. However, detection of the FANCM recruitment has been technically challenging so that its mechanism remains exclusive. Here, we successfully observed recruitment of FANCM at stalled forks using a newly developed protocol. We report that the FANCM recruitment depends upon its intrinsic DNA trans- locase activity, and its DNA-binding partner FAAP24. Moreover, it is dependent on the replication checkpoint kinase, ATR; but is independent of the FA core and FANCD2–FANCI complexes, two essential components of the FA pathway, indicating that the FANCM recruitment occurs downstream of ATR but upstream of the FA pathway. Interestingly, the recruitment of FANCM requires its direct interaction with Bloom syndrome complex composed of BLM helicase, Topoisomerase 3α, RMI1 and RMI2; as well as the helicase activity of BLM.
    [Show full text]
  • Recombinational DNA Repair and Human Disease Larry H
    Mutation Research 509 (2002) 49–78 Recombinational DNA repair and human disease Larry H. Thompson a,∗, David Schild b a Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory L-441, P.O. Box 808, Livermore, CA 94551-0808, USA b Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA Abstract We review the genes and proteins related to the homologous recombinational repair (HRR) pathway that are implicated in cancer through either genetic disorders that predispose to cancer through chromosome instability or the occurrence of somatic mutations that contribute to carcinogenesis. Ataxia telangiectasia (AT),Nijmegen breakage syndrome (NBS), and an ataxia-like disorder (ATLD), are chromosome instability disorders that are defective in the ataxia telangiectasia mutated (ATM), NBS, and Mre11 genes, respectively. These genes are critical in maintaining cellular resistance to ionizing radiation (IR), which kills largely by the production of double-strand breaks (DSBs). Bloom syndrome involves a defect in the BLM helicase, which seems to play a role in restarting DNA replication forks that are blocked at lesions, thereby promoting chromosome stability. The Werner syndrome gene (WRN) helicase, another member of the RecQ family like BLM, has very recently been found to help mediate homologous recombination. Fanconi anemia (FA) is a genetically complex chromosomal instability disorder involving seven or more genes, one of which is BRCA2. FA may be at least partially caused by the aberrant production of reactive oxidative species. The breast cancer-associated BRCA1 and BRCA2 proteins are strongly implicated in HRR; BRCA2 associates with Rad51 and appears to regulate its activity. We discuss in detail the phenotypes of the various mutant cell lines and the signaling pathways mediated by the ATM kinase.
    [Show full text]
  • Evaluation of Fanconi Anemia Genes in Familial Breast Cancer Predisposition
    [CANCER RESEARCH 63 8596–8599, December 15, 2003] Advances in Brief Evaluation of Fanconi Anemia Genes in Familial Breast Cancer Predisposition Sheila Seal,1 Rita Barfoot,1 Hiran Jayatilake,1 Paula Smith,2 Anthony Renwick,1 Linda Bascombe,1 Lesley McGuffog,2 D. Gareth Evans,3 Diana Eccles,4 The Breast Cancer Susceptibility Collaboration (UK), Douglas F. Easton,2 Michael R. Stratton,1,5 and Nazneen Rahman1 1Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey; 2Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratories, University of Cambridge, Cambridge; 3Department of Medical Genetics, St Mary’s Hospital, Manchester; 4Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton; and 5Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambs, United Kingdom Abstract underlying FA-A, FA-C, FA-E, FA-F, and FA-G were isolated by functional complementation of mitomycin-C-sensitive cells with Fanconi Anemia (FA) is an autosomal recessive syndrome character- cDNAs. FANCA was also identified by positional cloning, as was ized by congenital abnormalities, progressive bone marrow failure, and FANCD2 (reviewed in Refs. 1, 2). susceptibility to cancer. FA has eight known complementation groups and is caused by mutations in at least seven genes. Biallelic BRCA2 mutations The proteins encoded by FA genes are intimately related to each were shown recently to cause FA-D1. Monoallelic (heterozygous) BRCA2 other in molecular pathways involved in DNA repair, and FANCA, mutations confer a high risk of breast cancer and are a major cause of FANCC, FANCE, FANCF, and FANCG interact directly to form a familial breast cancer.
    [Show full text]
  • The Fanconi Anemia DNA Damage Repair Pathway in the Spotlight for Germline Predisposition to Colorectal Cancer
    European Journal of Human Genetics (2016) 24, 1501–1505 & 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1018-4813/16 www.nature.com/ejhg SHORT REPORT The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer Clara Esteban-Jurado1, Sebastià Franch-Expósito1, Jenifer Muñoz1, Teresa Ocaña1, Sabela Carballal1, Maria López-Cerón1, Miriam Cuatrecasas2, Maria Vila-Casadesús3, Juan José Lozano3, Enric Serra4, Sergi Beltran4, The EPICOLON Consortium, Alejandro Brea-Fernández5, Clara Ruiz-Ponte5, Antoni Castells1, Luis Bujanda6, Pilar Garre7, Trinidad Caldés7, Joaquín Cubiella8, Francesc Balaguer1 and Sergi Castellví-Bel*,1 Colorectal cancer (CRC) is one of the most common neoplasms in the world. Fanconi anemia (FA) is a very rare genetic disease causing bone marrow failure, congenital growth abnormalities and cancer predisposition. The comprehensive FA DNA damage repair pathway requires the collaboration of 53 proteins and it is necessary to restore genome integrity by efficiently repairing damaged DNA. A link between FA genes in breast and ovarian cancer germline predisposition has been previously suggested. We selected 74 CRC patients from 40 unrelated Spanish families with strong CRC aggregation compatible with an autosomal dominant pattern of inheritance and without mutations in known hereditary CRC genes and performed germline DNA whole- exome sequencing with the aim of finding new candidate germline predisposition variants. After sequencing and data analysis, variant prioritization selected only those very rare alterations, producing a putative loss of function and located in genes with a role compatible with cancer. We detected an enrichment for variants in FA DNA damage repair pathway genes in our familial CRC cohort as 6 families carried heterozygous, rare, potentially pathogenic variants located in BRCA2/FANCD1, BRIP1/FANCJ, FANCC, FANCE and REV3L/POLZ.
    [Show full text]
  • Chapter 1: the Fanconi Anemia DNA Repair Pathway
    Chapter 1 The Fanconi Anemia DNA Repair Pathway Introduction Discovery of the genes that cause Fanconi anemia (FA) and the role of FA proteins in regulating DNA repair have been active areas of research over the last 30 years. In the last edition of the clinical care guidelines published by the Fanconi Anemia Research Fund in 2014, 16 FA genes had been discovered. Researchers have now identified 23 genes that, when mutated, cause FA, including FANCA [1], FANCB [2], FANCC [3], FANCD1/BRCA2 [4], FANCD2 [5], FANCE [6], FANCF [7], FANCG [8], FANCI [9-11], FANCJ/BRIP1 [12], FANCL [13], FANCM [14- 17], FANCN/PALB2 [18], FANCO/RAD51C [19, 20 ], FANCP/SLX4 [21, 22], FANCQ/ERCC4 [23], FANCR/RAD51 [24, 25], FANCS/BRCA1 [26], FANCT/UBE2T [27-29], FANCU/XRCC2 [30], FANCV/REV7 [31], FANCW/RFWD3 [32], and FANCY/FAP100 [33]. Fanconi anemia is a multi-system disease caused by defects in the ability of cells to repair damaged DNA. Cells from patients with FA are unable to repair DNA interstrand crosslinks (ICLs), which are lesions that covalently link two strands of DNA and inhibit the essential cellular processes of DNA replication and transcription. This chapter provides a brief 9 summary of new research advancements on the molecular mechanisms of the FA DNA repair pathway. The relationship between the FA DNA repair pathway and toxins such as aldehydes and stem cell failure are also discussed. This chapter should not be considered a complete overview of all research on the pathway that has been published to date. Readers are encouraged to access references and review articles cited in the chapter for additional details.
    [Show full text]
  • Differential Mechanisms of Tolerance to Extreme Environmental
    www.nature.com/scientificreports OPEN Diferential mechanisms of tolerance to extreme environmental conditions in tardigrades Dido Carrero*, José G. Pérez-Silva , Víctor Quesada & Carlos López-Otín * Tardigrades, also known as water bears, are small aquatic animals that inhabit marine, fresh water or limno-terrestrial environments. While all tardigrades require surrounding water to grow and reproduce, species living in limno-terrestrial environments (e.g. Ramazzottius varieornatus) are able to undergo almost complete dehydration by entering an arrested state known as anhydrobiosis, which allows them to tolerate ionic radiation, extreme temperatures and intense pressure. Previous studies based on comparison of the genomes of R. varieornatus and Hypsibius dujardini - a less tolerant tardigrade - have pointed to potential mechanisms that may partially contribute to their remarkable ability to resist extreme physical conditions. In this work, we have further annotated the genomes of both tardigrades using a guided approach in search for novel mechanisms underlying the extremotolerance of R. varieornatus. We have found specifc amplifcations of several genes, including MRE11 and XPC, and numerous missense variants exclusive of R. varieornatus in CHEK1, POLK, UNG and TERT, all of them involved in important pathways for DNA repair and telomere maintenance. Taken collectively, these results point to genomic features that may contribute to the enhanced ability to resist extreme environmental conditions shown by R. varieornatus. Tardigrades are small
    [Show full text]