Curriculum Vitae
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Deficiency in the DNA Repair Protein ERCC1 Triggers a Link Between Senescence and Apoptosis in Human Fibroblasts and Mouse Skin
Lawrence Berkeley National Laboratory Recent Work Title Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin. Permalink https://escholarship.org/uc/item/73j1s4d1 Journal Aging cell, 19(3) ISSN 1474-9718 Authors Kim, Dong Eun Dollé, Martijn ET Vermeij, Wilbert P et al. Publication Date 2020-03-01 DOI 10.1111/acel.13072 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Received: 10 June 2019 | Revised: 7 October 2019 | Accepted: 30 October 2019 DOI: 10.1111/acel.13072 ORIGINAL ARTICLE Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin Dong Eun Kim1 | Martijn E. T. Dollé2 | Wilbert P. Vermeij3,4 | Akos Gyenis5 | Katharina Vogel5 | Jan H. J. Hoeijmakers3,4,5 | Christopher D. Wiley1 | Albert R. Davalos1 | Paul Hasty6 | Pierre-Yves Desprez1 | Judith Campisi1,7 1Buck Institute for Research on Aging, Novato, CA, USA Abstract 2Centre for Health Protection Research, ERCC1 (excision repair cross complementing-group 1) is a mammalian endonuclease National Institute of Public Health and that incises the damaged strand of DNA during nucleotide excision repair and inter- the Environment (RIVM), Bilthoven, The −/Δ Netherlands strand cross-link repair. Ercc1 mice, carrying one null and one hypomorphic Ercc1 3Department of Molecular Genetics, allele, have been widely used to study aging due to accelerated aging phenotypes Erasmus University Medical Center, −/Δ Rotterdam, The Netherlands in numerous organs and their shortened lifespan. Ercc1 mice display combined 4Princess Máxima Center for Pediatric features of human progeroid and cancer-prone syndromes. -
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. -
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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. -
Neurodegeneration in Accelerated Aging
DOCTOR OF MEDICAL SCIENCE DANISH MEDICAL JOURNAL Neurodegeneration in Accelerated Aging Morten Scheibye-Knudsen This review has been accepted as a thesis together with 7 previously published pa- pers by the University of Copenhagen, October 16, 2014 and defended on January 14, 2016 Official opponents: Alexander Bürkle, University of Konstanz Lars Eide, University of Oslo Correspondence: Center for Healthy Aging, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen E-mail: [email protected] Dan Med J 2016;63(11):B5308 INTRODUCTION The global elderly population has been progressively increasing throughout the 20th century and this growth is projected to per- sist into the late 21st century resulting in 20% of the total world population being aged 65 or more by the year 2100 (Figure 1). 80% of the total cost of health care is accrued after 40 years of Figure 2. The phenotype of human aging. age where chronic diseases become prevalent [1, 2]. With an ex- that appear to regulate the aging process [4,5]. These include the ponential increase in health care costs, it follows that the chronic insulin and IGF-1 signaling cascades [4], protein synthesis and diseases that accumulate in an aging population poses a serious quality control [6], regulation of cell proliferation through factors socioeconomic problem. Finding treatments to age related dis- such as mTOR [7], stem cell maintenance 8 as well as mitochon- eases, therefore becomes increasingly more pertinent as the pop- drial preservation [9]. Most of these pathways are conserved ulation ages. Even more so since there appears to be a continu- through evolution and appear to regulate aging in many lower or- ous increase in the prevalence of chronic diseases in the aging ganisms. -
Hyper Telomere Recombination Accelerates Replicative Senescence and May Promote Premature Aging
Hyper telomere recombination accelerates replicative senescence and may promote premature aging R. Tanner Hagelstroma,b, Krastan B. Blagoevc,d, Laura J. Niedernhofere, Edwin H. Goodwinf, and Susan M. Baileya,1 aDepartment of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523-1618; bPharmaceutical Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004; cNational Science Foundation, Arlington, VA 22230; dDepartment of Physics Cavendish Laboratory, Cambridge University, Cambridge CB3 0HE, United Kingdom; eDepartment of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine and Cancer Institute, Pittsburgh, PA 15261; and fKromaTiD Inc., Fort Collins, CO 80524 Edited* by José N. Onuchic, University of California San Diego, La Jolla, CA, and approved August 3, 2010 (received for review May 7, 2010) Werner syndrome and Bloom syndrome result from defects in the cell-cycle arrest known as senescence (12). Most human tissues lack RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and sufficient telomerase activity to maintain telomere length through- display premature aging phenotypes. Similarly, XFE progeroid out life, limiting cell division potential. The majority of cancers syndrome results from defects in the ERCC1-XPF DNA repair endo- circumvent this tumor-suppressor mechanism by reactivating telo- nuclease. To gain insight into the origin of cellular senescence and merase (13), thus removing telomere shortening as a barrier to human aging, we analyzed the dependence of sister chromatid continuous proliferation. In some situations, a recombination- exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telo- based mechanism known as “alternative lengthening of telomeres” meric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, (ALT) maintains telomere length in the absence of telomerase (14). -
Werner Syndrome Protein Participates in a Complex with RAD51, RAD54
Erratum Werner syndrome protein participates in a complex with RAD51, RAD54, RAD54B and ATR in response to ICL-induced replication arrest Marit Otterlei, Per Bruheim, Byungchan Ahn, Wendy Bussen, Parimal Karmakar, Kathy Baynton and Vilhelm A. Bohr Journal of Cell Science 119, 5215 (2006) doi:10.1242/jcs.03359 There was an error in the first e-press version of the article published in J. Cell Sci. 119, 5137-5146. The first e-press version of this article gave the page range as 5114-5123, whereas it should have been 5137-5146. We apologise for this mistake. Research Article 5137 Werner syndrome protein participates in a complex with RAD51, RAD54, RAD54B and ATR in response to ICL-induced replication arrest Marit Otterlei1,2,*, Per Bruheim1,3,§, Byungchan Ahn1,4,§, Wendy Bussen5, Parimal Karmakar1,6, Kathy Baynton7 and Vilhelm A. Bohr1 1Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224, USA 2Department of Cancer Research and Molecular Medicine, Laboratory Centre, Faculty of Medicine, Norwegian University of Science and Technology, Erling Skjalgsons gt. 1, N-7006 Trondheim, Norway 3Department of Biotechnology, Norwegian University of Science and Technology, N-7491 Trondheim, Norway 4Department of Life Sciences, University of Ulsan, Ulsan 680-749, Korea 5Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 333 Cedar St, SHM-C130, New Haven, CT 06515, USA 6Department of Life Science and Biotechnology, Jadavpur University, Kolkata-700 032, WB, -
Human DNA Repair Genes Relatively Late-Diverging, Major Eukaryotic Taxa Whose Exact Order of Radiation Is Difficult to Deter- Richard D
A NALYSIS OF G ENOMIC I NFORMATION likely GTPases, as indicated by the activity of CIITA 27. L. Aravind, H. Watanabe, D. J. Lipman, E. V. Koonin, of the Integrated Protein Index and A. Uren for critical and HET-E [E. V. Koonin, L. Aravind, Trends Biochem. Proc. Natl. Acad. Sci. U.S.A. 97, 11319 (2000). reading of the manuscript and useful comments. The Sci. 25, 223 (2000)]. 28. J. R. Brown, W. F. Doolittle, Microbiol. Mol. Biol. Rev. release of the unpublished WormPep data set by The 14. T. L. Beattie, W. Zhou, M. O. Robinson, L. Harrington, 61, 456 (1997). Sanger Center is acknowledged and greatly appreciated. Curr. Biol. 8, 177 (1998). 29. We thank E. Birney and A. Bateman (The Sanger Center, 15. E. Diez, Z. Yaraghi, A. MacKenzie, P. Gros, J. Immunol. Hinxton, UK) for kindly providing the preliminary version 25 October 2000; accepted 18 January 2001 164, 1470 (2000). 16. A. M. Verhagen et al., Cell 102, 43 (2000). 17. L. Goyal, K. McCall, J. Agapite, E. Hartwieg, H. Steller, EMBO J. 19, 589 (2000). 18. The eukaryotic crown group is the assemblage of Human DNA Repair Genes relatively late-diverging, major eukaryotic taxa whose exact order of radiation is difficult to deter- Richard D. Wood,1* Michael Mitchell,2 John Sgouros,2 mine with confidence. The crown group includes the 1 multicellular eukaryotes (animals, fungi, and plants) Tomas Lindahl and some unicellular eukaryotic lineages such as slime molds and Acanthamoebae [A. H. Knoll, Science 256, 622 (1992); S. Kumar, A. Rzhetsky, J. Mol. -
Potentially Functional Single Nucleotide Polymorphisms in the Core Nucleotide Excision Repair Genes and Risk of Squamous Cell Carcinoma of the Head and Neck
1633 Potentially Functional Single Nucleotide Polymorphisms in the Core Nucleotide Excision Repair Genes and Risk of Squamous Cell Carcinoma of the Head and Neck Jiaze An,1 Zhensheng Liu,1 Zhibin Hu,1 Guojun Li,1 Li-E Wang,1 Erich M. Sturgis,1,2 AdelK. El-Naggar, 2,3 Margaret R. Spitz,1 and Qingyi Wei1 Departments of 1Epidemiology, 2Head and Neck Surgery, and 3Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas Abstract Susceptibility to cancer has been associated with DNA SCCHN risk (adjusted odds ratio, 1.65; 95% confidence repair capacity, a global reflection of all functional variants, interval, 1.16-2.36). In analysis of the joint effects, the most of which are relatively rare. Among the 1,098 single number of observed risk genotypes was associated with nucleotide polymorphisms (SNP) identified in the eight SCCHN risk in a dose-response manner (P for trend = 0.017) core nucleotide excision repair genes, only a few are and those who carried four or more risk genotypes exhibited common nonsynonymous or regulatory SNPs that are a borderline significant 1.23-fold increased SCCHN risk potentially functional. We tested the hypothesis that seven (adjusted odds ratio, 1.23; 95% confidence interval, 0.99-1.53). selected common nonsynonymous and regulatory variants In the stratified analysis, the dichotomized combined effect in the nucleotide excision repair core genes are associated of the seven SNPs was slightly more evident among older with risk of squamous cell carcinoma of the head and neck subjects, women, and laryngeal cancer. These findings (SCCHN) in a hospital-based, case-control study of 829 suggest that these potentially functional SNPs may collec- SCCHN cases and 854 cancer-free controls. -
Muts Homologue 2 and the Long-Term Benefit of Adjuvant Chemotherapy in Lung Cancer
Published OnlineFirst February 9, 2010; DOI: 10.1158/1078-0432.CCR-09-2204 Published Online First on February 9, 2010 as 10.1158/1078-0432.CCR-09-2204 Clinical Imaging, Diagnosis, Prognosis Cancer Research MutS Homologue 2 and the Long-term Benefit of Adjuvant Chemotherapy in Lung Cancer Nermine S. Kamal1, Jean-Charles Soria1,2, Jean Mendiboure3, David Planchard1, Ken A. Olaussen1, Vanessa Rousseau3, Helmut Popper5, Robert Pirker6, Pascale Bertrand7, Ariane Dunant3, Thierry Le Chevalier4, Martin Filipits6, and Pierre Fouret1,8 for the International Adjuvant Lung Trial-Bio investigators Abstract Purpose: We sought to determine the long-term (median follow-up, 7.5 years) predictive power of human MutS homologue 2 (MSH2) immunohistochemical expression in patients who enrolled in the International Adjuvant Lung Trial. Experimental design: We tested the interaction between MSH2 and the allocated treatment (chemo- therapy versus observation) in a Cox model adjusted on clinicopathologic variables. The significance level was set at 0.01. Results: MSH2 levels were low in 257 (38%) and high in 416 (62%) tumors. The benefit from che- motherapy was likely different according to MSH2 (interaction test, P = 0.06): there was a trend for che- motherapy to prolong overall survival when MSH2 was low [hazard ratio (HR), 0.76; 95% confidence interval (95% CI), 0.59-0.97; P = 0.03], but not when MSH2 was high (HR, 1.12; 95% CI, 0.81-1.55; P = 0.48). In the control arm, the HR was 0.66 (95% CI, 0.49-0.90; P = 0.01) when MSH2 was high. When combining MSH2 with excision repair cross-complementing group 1 (ERCC1) into four subgroups, the benefit of chemotherapy decreased with the number of markers expressed at high levels (P = 0.01). -
University of Cincinnati
UNIVERSITY OF CINCINNATI _____________ , 20 _____ I,______________________________________________, hereby submit this as part of the requirements for the degree of: ________________________________________________ in: ________________________________________________ It is entitled: ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ Approved by: ________________________ ________________________ ________________________ ________________________ ________________________ BLM is a Suppressor of DNA Recombination A dissertation submitted to the Division of Research and Advanced Studies Of the University of Cincinnati In partial fulfillment of the Requirements for the degree of Doctorate of Philosophy (Ph.D.) In the Department of Molecular Genetics, Microbiology, and Biochemistry Of the College of Arts and Sciences 2002 by Joel E. Straughen B.S., The Ohio State University, 1985 M.D., University of Cincinnati, 2002 Committee Chair: Joanna Groden, Ph.D. i ABSTRACT Bloom’s syndrome (BS) is a rare, recessive chromosome breakage disorder characterized by small stature, sun sensitivity, facial erythema, immunodeficiency, female subfertility, male infertility, and a predisposition to a variety of cancers. When this body of work was started, the gene for Bloom’s syndrome (BLM)hadyettobe identified. This work presents characterization of the genomic region at BLM and the identification of BLM. With the cloning -
The Werner Syndrome Protein Is Distinguished from the Bloom Syndrome Protein by Its Capacity to Tightly Bind Diverse DNA Structures
The Werner Syndrome Protein Is Distinguished from the Bloom Syndrome Protein by Its Capacity to Tightly Bind Diverse DNA Structures Ashwini Kamath-Loeb1, Lawrence A. Loeb1, Michael Fry2* 1 Department of Pathology, The Gottstein Memorial Cancer Research Center, University of Washington, Seattle, Washington, United States of America, 2 Department of Biochemistry, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel Abstract Loss of Werner syndrome helicase-exonuclease (WRN) or of its homolog Bloom syndrome helicase (BLM) results in different inherited disorders. Whereas Werner syndrome is characterized by premature onset of aging and age-associated diseases, Bloom syndrome involves developmental abnormalities and increased predisposition to diverse malignancies. To identify biochemical differences between WRN and BLM that might contribute to the dissimilar outcomes of their loss, we compared their abilities to unwind and bind in vitro diverse DNA structures. Full-length recombinant WRN and BLM proteins expressed in and purified from Sf9 insect cells unwound to comparable extents and with similar Km values partial DNA duplex, splayed arm DNA and G’2 bimolecular quadruplex DNA. However, WRN resolved bubble DNA ,25-fold more efficiently than BLM. The two enzymes were mainly distinguished by their contrasting abilities to bind DNA. WRN bound partial duplexes, bubble and splayed arm DNA and G’2 bimolecular and G4 four-molecular quadruplexes with dissociation constants of 0.25 to 25 nM. By contrast, BLM formed substantial complexes with only G4 quadruplex DNA while binding only marginally other DNA structures. We raise the possibility that in addition to its enzymatic activities WRN may act as a scaffold for the assembly on DNA of additional DNA processing proteins. -
Messenger RNA Levels of XPAC and ERCC1 in Ovarian Cancer Tissue Correlate with Response to Platinum-Based Chemotherapy
Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. M Dabholkar, … , J J Yu, E Reed J Clin Invest. 1994;94(2):703-708. https://doi.org/10.1172/JCI117388. Research Article Nucleotide excision repair is a DNA repair pathway that is highly conserved in nature, with analogous repair systems described in Escherichia coli, yeast, and mammalian cells. The rate-limiting step, DNA damage recognition and excision, is effected by the protein products of the genes ERCC1 and XPAC. We therefore assessed mRNA levels of ERCC1 and XPAC in malignant ovarian cancer tissues from 28 patients that were harvested before the administration of platinum- based chemotherapy. Cancer tissues from patients whose tumors were clinically resistant to therapy (n = 13) showed greater levels of total ERCC1 mRNA (P = 0.059), full length transcript of ERCC1 mRNA (P = 0.026), and XPAC mRNA (P = 0.011), as compared with tumor tissues from those individuals clinically sensitive to therapy (n = 15). In 19 of these tissues, the percentage of alternative splicing of ERCC1 mRNA was assessed. ERCC1 splicing was highly variable, with no difference observed between responders and nonresponders. The alternatively spliced species constituted 2-58% of the total ERCC1 mRNA in responders (median = 18%) and 4-71% in nonresponders (median = 13%). These data suggest greater activity of the DNA excision repair genes ERCC1 and XPAC in ovarian cancer tissues of patients clinically resistant to platinum compounds. These data also