Structure and Function of the Human Recq DNA Helicases
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Variant Requirements for DNA Repair Proteins in Cancer Cell Lines That Use
Variant requirements for DNA repair proteins in cancer cell lines that use alternative lengthening of telomere mechanisms of elongation DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Alaina Rae Martinez Biomedical Sciences Graduate Program The Ohio State University 2016 Dissertation Committee: Dr. Jeffrey D. Parvin, Advisor Dr. Joanna Groden Dr. Amanda E. Toland Dr. Kay F. Huebner Copyright by Alaina Rae Martinez 2016 Abstract The human genome relies on DNA repair proteins and the telomere to maintain genome stability. Genome instability is recognized as a hallmark of cancer, as is limitless replicative capacity. Cancer cells require telomere maintenance to enable this uncontrolled growth. Most often telomerase is activated, although a subset of human cancers depend on recombination-based mechanisms known as Alternative Lengthening of Telomeres (ALT). ALT depends invariably on recombination and its associated DNA repair proteins to extend telomeres. This study tested the hypothesis that the requirement for those requisite recombination proteins include other types of DNA repair proteins. These functions were tested in ALT cell lines using C-circle abundance as a marker of ALT. The requirement for homologous recombination proteins and other DNA repair proteins varied between ALT cell lines compared. Several proteins essential for homologous recombination were dispensable for C-circle production in some ALT cell lines, while proteins grouped into excision DNA repair processes were required for C- circle production. The MSH2 mismatch repair protein was required for telomere recombination by intertelomeric exchange. In sum, our study suggests that ALT proceeds by multiple mechanisms that differ between human cancer cell lines and that some of these depend on DNA repair proteins not associated with homologous recombination pathways. -
Atlas Antibodies in Breast Cancer Research Table of Contents
ATLAS ANTIBODIES IN BREAST CANCER RESEARCH TABLE OF CONTENTS The Human Protein Atlas, Triple A Polyclonals and PrecisA Monoclonals (4-5) Clinical markers (6) Antibodies used in breast cancer research (7-13) Antibodies against MammaPrint and other gene expression test proteins (14-16) Antibodies identified in the Human Protein Atlas (17-14) Finding cancer biomarkers, as exemplified by RBM3, granulin and anillin (19-22) Co-Development program (23) Contact (24) Page 2 (24) Page 3 (24) The Human Protein Atlas: a map of the Human Proteome The Human Protein Atlas (HPA) is a The Human Protein Atlas consortium cell types. All the IHC images for Swedish-based program initiated in is mainly funded by the Knut and Alice the normal tissue have undergone 2003 with the aim to map all the human Wallenberg Foundation. pathology-based annotation of proteins in cells, tissues and organs expression levels. using integration of various omics The Human Protein Atlas consists of technologies, including antibody- six separate parts, each focusing on References based imaging, mass spectrometry- a particular aspect of the genome- 1. Sjöstedt E, et al. (2020) An atlas of the based proteomics, transcriptomics wide analysis of the human proteins: protein-coding genes in the human, pig, and and systems biology. mouse brain. Science 367(6482) 2. Thul PJ, et al. (2017) A subcellular map of • The Tissue Atlas shows the the human proteome. Science. 356(6340): All the data in the knowledge resource distribution of proteins across all eaal3321 is open access to allow scientists both major tissues and organs in the 3. -
Plugged Into the Ku-DNA Hub: the NHEJ Network Philippe Frit, Virginie Ropars, Mauro Modesti, Jean-Baptiste Charbonnier, Patrick Calsou
Plugged into the Ku-DNA hub: The NHEJ network Philippe Frit, Virginie Ropars, Mauro Modesti, Jean-Baptiste Charbonnier, Patrick Calsou To cite this version: Philippe Frit, Virginie Ropars, Mauro Modesti, Jean-Baptiste Charbonnier, Patrick Calsou. Plugged into the Ku-DNA hub: The NHEJ network. Progress in Biophysics and Molecular Biology, Elsevier, 2019, 147, pp.62-76. 10.1016/j.pbiomolbio.2019.03.001. hal-02144114 HAL Id: hal-02144114 https://hal.archives-ouvertes.fr/hal-02144114 Submitted on 29 May 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Progress in Biophysics and Molecular Biology xxx (xxxx) xxx Contents lists available at ScienceDirect Progress in Biophysics and Molecular Biology journal homepage: www.elsevier.com/locate/pbiomolbio Plugged into the Ku-DNA hub: The NHEJ network * Philippe Frit a, b, Virginie Ropars c, Mauro Modesti d, e, Jean Baptiste Charbonnier c, , ** Patrick Calsou a, b, a Institut de Pharmacologie et Biologie Structurale, IPBS, Universite de Toulouse, CNRS, UPS, Toulouse, France b Equipe Labellisee Ligue Contre -
Regulation of DNA Cross-Link Repair by the Fanconi Anemia/BRCA Pathway
Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway Hyungjin Kim and Alan D. D’Andrea1 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA The maintenance of genome stability is critical for sur- and quadradials, a phenotype widely used as a diagnostic vival, and its failure is often associated with tumorigen- test for FA. esis. The Fanconi anemia (FA) pathway is essential for At least 15 FA gene products constitute a common the repair of DNA interstrand cross-links (ICLs), and a DNA repair pathway, the FA pathway, which resolves germline defect in the pathway results in FA, a cancer ICLs encountered during replication (Fig. 1A). Specifi- predisposition syndrome driven by genome instability. cally, eight FA proteins (FANCA/B/C/E/F/G/L/M) form Central to this pathway is the monoubiquitination of a multisubunit ubiquitin E3 ligase complex, the FA core FANCD2, which coordinates multiple DNA repair activ- complex, which activates the monoubiquitination of ities required for the resolution of ICLs. Recent studies FANCD2 and FANCI after genotoxic stress or in S phase have demonstrated how the FA pathway coordinates three (Wang 2007). The FANCM subunit initiates the pathway critical DNA repair processes, including nucleolytic in- (Fig. 1B). It forms a heterodimeric complex with FAAP24 cision, translesion DNA synthesis (TLS), and homologous (FA-associated protein 24 kDa), and the complex resem- recombination (HR). Here, we review recent advances in bles an XPF–ERCC1 structure-specific endonuclease pair our understanding of the downstream ICL repair steps (Ciccia et al. -
AN INVESTIGATION of the ROLE of PAK6 in TUMORIGENESIS By
AN INVESTIGATION OF THE ROLE OF PAK6 IN TUMORIGENESIS by JoAnn Roberts A Thesis Submitted to the Faculty of The Charles E. Schmidt College of Medicine In Partial Fulfillment of the Requirements for the Degree of Master of Science Florida Atlantic University Boca Raton, Florida August 2012 ACKNOWLEDGMENTS This material is based upon work supported by the National Science Foundation under Grant No. DGE: 0638662. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. I would like to thank and acknowledge my thesis advisor, Dr. Michael Lu, for his support and guidance throughout the writing of this thesis and design of experiments in this manuscript. I would also like to thank my colleagues for assistance in various trouble-shooting circumstances. Last, but certainly not least, I would like to thank my family and friends for their support in the pursuit of my graduate studies. iii ABSTRACT Author: JoAnn Roberts Title: An Investigation of the Role of PAK6 in Tumorigenesis Institution: Florida Atlantic University Thesis Advisor: Dr. Michael Lu Degree: Master of Science Year: 2012 The function and role of PAK6, a serine/threonine kinase, in cancer progression has not yet been clearly identified. Several studies reveal that PAK6 may participate in key changes contributing to cancer progression such as cell survival, cell motility, and invasiveness. Based on the membrane localization of PAK6 in prostate and breast cancer cells, we speculated that PAK6 plays a role in cancer progression cells by localizing on the membrane and modifying proteins linked to motility and proliferation. -
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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. -
17 January 2001
Running Title: DNA Recombination and Repair in the Archaea DNA Recombination and Repair in the Archaea Erica M. Seitz, Cynthia A. Haseltine, and Stephen C. Kowalczykowski* Sections of Microbiology and of Molecular and Cellular Biology Center for Genetics and Development University of California, Davis Davis, CA 95616-8665 * Corresponding author: Section of Microbiology One Shields Avenue Hutchison Hall University of California, Davis Davis, CA 95616-8665 Phone: (530)752-5938 Fax: (530)752-5939 email: [email protected] 1 Abstract The ability to repair DNA damage is crucial to all organisms. Much of what we learned about these processes was gained from studies carried out in Bacteria, especially in Escherichia coli, or Eucarya, particularly in the yeast Saccharomyces cerevisiae. The repair of DNA damage occurs by at least four different pathways: direct reversal of DNA damage, excision of damaged nucleotides (nucleotide excision repair or NER) or bases (base excision repair or BER), excision of misincorporated nucleotides (mismatch repair or MMR), and recombinational repair. Proteins involved in these processes have recently been identified in the third domain of life, the Archaea. Here we present a summary of DNA repair proteins in both the Bacteria and Eucarya, and discuss similarities and differences between these two domains and what is currently known in the Archaea. 2 I. Introduction DNA is subjected daily to considerable environmental and endogenous damage, which challenges both the integrity of the essential information that it contains and its ability to be transferred to future generations. All cells, however, are prepared to handle damage to the genome through an extensive DNA repair system, thus underscoring the importance of this process in cell survival. -
The Bloom Syndrome Protein Limits the Lethality Associated with RAD51 Deficiency
Published OnlineFirst March 9, 2010; DOI: 10.1158/1541-7786.MCR-09-0534 Molecular DNA Damage and Cellular Stress Responses Cancer Research The Bloom Syndrome Protein Limits the Lethality Associated with RAD51 Deficiency Kenza Lahkim Bennani-Belhaj1,2, Sébastien Rouzeau1,2, Géraldine Buhagiar-Labarchède1,2, Pauline Chabosseau1,2, Rosine Onclercq-Delic1,2, Emilie Bayart1, Fabrice Cordelières3,4, Jérôme Couturier5,6, and Mounira Amor-Guéret1,2 Abstract Little is known about the functional interaction between the Bloom's syndrome protein (BLM) and the re- combinase RAD51 within cells. Using RNA interference technology, we provide the first demonstration that RAD51 acts upstream from BLM to prevent anaphase bridge formation. RAD51 downregulation was associated with an increase in the frequency of BLM-positive anaphase bridges, but not of BLM-associated ultrafine bridges. Time-lapse live microscopy analysis of anaphase bridge cells revealed that BLM promoted cell survival in the absence of Rad51. Our results directly implicate BLM in limiting the lethality associated with RAD51 deficiency through the processing of anaphase bridges resulting from the RAD51 defect. These findings provide insight into the molecular basis of some cancers possibly associated with variants of the RAD51 gene family. Mol Cancer Res; 8(3); 385–94. ©2010 AACR. Introduction cently, SUMOylation of BLM has been shown to regulate its association with RAD51 and its function in HR-medi- Bloom's syndrome displays one of the strongest known ated repair of damaged replication forks (13). In several correlations between chromosomal instability and a high models, it has been proposed that BLM restarts replication risk of cancer at an early age. -
The Role of Nucleotide Excision Repair in Restoring Replication Following UV-Induced Damage in Escherichia Coli
Portland State University PDXScholar Dissertations and Theses Dissertations and Theses Summer 1-1-2012 The Role of Nucleotide Excision Repair in Restoring Replication Following UV-Induced Damage in Escherichia coli Kelley Nicole Newton Portland State University Follow this and additional works at: https://pdxscholar.library.pdx.edu/open_access_etds Part of the Biology Commons, and the Cell Biology Commons Let us know how access to this document benefits ou.y Recommended Citation Newton, Kelley Nicole, "The Role of Nucleotide Excision Repair in Restoring Replication Following UV- Induced Damage in Escherichia coli" (2012). Dissertations and Theses. Paper 767. https://doi.org/10.15760/etd.767 This Thesis is brought to you for free and open access. It has been accepted for inclusion in Dissertations and Theses by an authorized administrator of PDXScholar. Please contact us if we can make this document more accessible: [email protected]. The Role of Nucleotide Excision Repair in Restoring Replication Following UV-Induced Damage in Escherichia coli by Kelley Nicole Newton A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in Biology Thesis Committee: Justin Courcelle, Chair Michael Bartlett Jeffrey Singer Portland State University 2012 ABSTRACT Following low levels of UV exposure, Escherichia coli cells deficient in nucleotide excision repair recover and synthesize DNA at near wild type levels, an observation that formed the basis of the post replication recombination repair model. In this study, we characterized the DNA synthesis that occurs following UV-irradiation in the absence of nucleotide excision repair and show that although this synthesis resumes at near wild type levels, it is coincident with a high degree of cell death. -
Genomic Profiling Reveals High Frequency of DNA Repair Genetic
www.nature.com/scientificreports OPEN Genomic profling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer Reham Abdel‑Wahab1,9, Timothy A. Yap2, Russell Madison4, Shubham Pant1,2, Matthew Cooke4, Kai Wang4,5,7, Haitao Zhao8, Tanios Bekaii‑Saab6, Elif Karatas1, Lawrence N. Kwong3, Funda Meric‑Bernstam2, Mitesh Borad6 & Milind Javle1,10* DNA repair gene aberrations (GAs) occur in several cancers, may be prognostic and are actionable. We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (PD‑1), and its ligand (PD‑L1) expression. Comprehensive genomic profling (CGP) of 760 GBC was performed. We investigated GAs in 19 DNA repair genes including direct DNA repair genes (ATM, ATR , BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, and RAD50) and caretaker genes (BAP1, CDK12, MLL3, TP53, and BLM) and classifed patients into 3 groups based on TMB level: low (< 5.5 mutations/Mb), intermediate (5.5–19.5 mutations/Mb), and high (≥ 19.5 mutations/Mb). We assessed MSI status and PD‑1 & PD‑L1 expression. 658 (86.6%) had at least 1 actionable GA. Direct DNA repair gene GAs were identifed in 109 patients (14.2%), while 476 (62.6%) had GAs in caretaker genes. Both direct and caretaker DNA repair GAs were signifcantly associated with high TMB (P = 0.0005 and 0.0001, respectively). Tumor PD‑L1 expression was positive in 119 (15.6%), with 17 (2.2%) being moderate or high. DNA repair GAs are relatively frequent in GBC and associated with coexisting actionable mutations and a high TMB. -
Encyclopedia of Life Sciences
DNA repair: Disorders Lehmann, Alan R and O‟Driscoll, Mark Alan R Lehmann and Mark O‟Driscoll Genome Damage and Stability Centre University of Sussex Falmer, Brighton BN1 9RQ UK Encyclopedia of Life Sciences DNA Repair: Disorders Abstract Deoxyribonucleic acid inside cells is being damaged continually. Cells have evolved a series of complex mechanisms to repair all types of damage. Deficiencies in these repair pathways can result in several different genetic disorders. In many cases these are associated with a greatly elevated incidence of specific cancers. Other disorders do not show increased cancer susceptibility, but instead they present with neurological abnormalities or immune defects. Features of premature ageing also often result. These disorders indicate that DNA repair and damage response processes protect us from cancer and are important for the maintenance of a healthy condition. Keywords: UV light; xeroderma pigmentosum; ataxia telangiectasia; cancer; immunodeficiency; DNA repair. Key concepts DNA is damaged continually from both endogenous and exogenous sources. Cells have evolved many different ways for repairing different types of damage Genetic defects in these pathways result in different disorders Defective DNA repair often results in an increased mutation frequency and consequent elevated incidence of cancer. Many of the DNA repair disorders are highly cancer-prone. The central nervous system appears to be particularly sensitive to DNA breaks. Several disorders caused by defective break repair are associated with neurological abnormalities including mental retardation, ataxia and microcephaly. Development of immunological diversity uses some of the enzymes required to repair double-strand breaks. Disorders caused by defects in this process are associated with immune deficiencies. -
Further Insights Into the Regulation of the Fanconi Anemia FANCD2 Protein
University of Rhode Island DigitalCommons@URI Open Access Dissertations 2015 Further Insights Into the Regulation of the Fanconi Anemia FANCD2 Protein Rebecca Anne Boisvert University of Rhode Island, [email protected] Follow this and additional works at: https://digitalcommons.uri.edu/oa_diss Recommended Citation Boisvert, Rebecca Anne, "Further Insights Into the Regulation of the Fanconi Anemia FANCD2 Protein" (2015). Open Access Dissertations. Paper 397. https://digitalcommons.uri.edu/oa_diss/397 This Dissertation is brought to you for free and open access by DigitalCommons@URI. It has been accepted for inclusion in Open Access Dissertations by an authorized administrator of DigitalCommons@URI. For more information, please contact [email protected]. FURTHER INSIGHTS INTO THE REGULATION OF THE FANCONI ANEMIA FANCD2 PROTEIN BY REBECCA ANNE BOISVERT A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CELL AND MOLECULAR BIOLOGY UNIVERSITY OF RHODE ISLAND 2015 DOCTOR OF PHILOSOPHY DISSERTATION OF REBECCA ANNE BOISVERT APPROVED: Dissertation Committee: Major Professor Niall Howlett Paul Cohen Becky Sartini Nasser H. Zawia DEAN OF THE GRADUATE SCHOOL UNIVERSITY OF RHODE ISLAND 2015 ABSTRACT Fanconi anemia (FA) is a rare autosomal and X-linked recessive disorder, characterized by congenital abnormalities, pediatric bone marrow failure and cancer susceptibility. FA is caused by biallelic mutations in any one of 16 genes. The FA proteins function cooperatively in the FA-BRCA pathway to repair DNA interstrand crosslinks (ICLs). The monoubiquitination of FANCD2 and FANCI is a central step in the activation of the FA-BRCA pathway and is required for targeting these proteins to chromatin.