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Homologous Repair of DNA Damage and Tumorigenesis: the BRCA Connection
Oncogene (2002) 21, 8981 – 8993 ª 2002 Nature Publishing Group All rights reserved 0950 – 9232/02 $25.00 www.nature.com/onc Homologous repair of DNA damage and tumorigenesis: the BRCA connection Maria Jasin*,1 1Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA Homologous recombination has been recognized in recent Tirkkonen et al., 1997; Turner et al., 2002; Xu et al., years to be an important DNA repair pathway in 1999), are sensitive to DNA damaging agents (Bhatta- mammalian cells, for such damage as chromosomal charyya et al., 2000; Connor et al., 1997; Gowen et al., double-strand breaks. Cells mutated for the genes 1998; Kraakman-van der Zwet et al., 2002; Morimatsu involved in the hereditary breast and ovarian cancer et al., 1998; Moynahan et al., 2001a; Scully et al., 1999; susceptibility syndromes, i.e. BRCA1 and BRCA2, show Sharan et al., 1997; Shen et al., 1998; Zhong et al., defects in DNA repair by homologous recombination, 1999), including ionizing radiation and cross-linking implicating this repair pathway in protecting individuals agents, and have elevated mutation rates (Kraakman- against tumorigenesis. This review summarizes recent van der Zwet et al., 2002; Tutt et al., 2002). During S advances in our understanding of BRCA1 and BRCA2 in phase or upon treatment of cells with DNA damaging DNA repair, as well as insight into these proteins agents or replication inhibitors, both proteins are in gleaned from structure determination of domains of these nuclear foci along with several other proteins involved proteins and the broader evolutionary conservation than in the damage response, including the DNA repair previously appreciated. -
Seq2pathway Vignette
seq2pathway Vignette Bin Wang, Xinan Holly Yang, Arjun Kinstlick May 19, 2021 Contents 1 Abstract 1 2 Package Installation 2 3 runseq2pathway 2 4 Two main functions 3 4.1 seq2gene . .3 4.1.1 seq2gene flowchart . .3 4.1.2 runseq2gene inputs/parameters . .5 4.1.3 runseq2gene outputs . .8 4.2 gene2pathway . 10 4.2.1 gene2pathway flowchart . 11 4.2.2 gene2pathway test inputs/parameters . 11 4.2.3 gene2pathway test outputs . 12 5 Examples 13 5.1 ChIP-seq data analysis . 13 5.1.1 Map ChIP-seq enriched peaks to genes using runseq2gene .................... 13 5.1.2 Discover enriched GO terms using gene2pathway_test with gene scores . 15 5.1.3 Discover enriched GO terms using Fisher's Exact test without gene scores . 17 5.1.4 Add description for genes . 20 5.2 RNA-seq data analysis . 20 6 R environment session 23 1 Abstract Seq2pathway is a novel computational tool to analyze functional gene-sets (including signaling pathways) using variable next-generation sequencing data[1]. Integral to this tool are the \seq2gene" and \gene2pathway" components in series that infer a quantitative pathway-level profile for each sample. The seq2gene function assigns phenotype-associated significance of genomic regions to gene-level scores, where the significance could be p-values of SNPs or point mutations, protein-binding affinity, or transcriptional expression level. The seq2gene function has the feasibility to assign non-exon regions to a range of neighboring genes besides the nearest one, thus facilitating the study of functional non-coding elements[2]. Then the gene2pathway summarizes gene-level measurements to pathway-level scores, comparing the quantity of significance for gene members within a pathway with those outside a pathway. -
(TEX) Genes: a Review Focused on Spermatogenesis and Male Fertility
Bellil et al. Basic and Clinical Andrology (2021) 31:9 https://doi.org/10.1186/s12610-021-00127-7 REVIEW ARTICLE Open Access Human testis-expressed (TEX) genes: a review focused on spermatogenesis and male fertility Hela Bellil1, Farah Ghieh2,3, Emeline Hermel2,3, Béatrice Mandon-Pepin2,3 and François Vialard1,2,3* Abstract Spermatogenesis is a complex process regulated by a multitude of genes. The identification and characterization of male-germ-cell-specific genes is crucial to understanding the mechanisms through which the cells develop. The term “TEX gene” was coined by Wang et al. (Nat Genet. 2001; 27: 422–6) after they used cDNA suppression subtractive hybridization (SSH) to identify new transcripts that were present only in purified mouse spermatogonia. TEX (Testis expressed) orthologues have been found in other vertebrates (mammals, birds, and reptiles), invertebrates, and yeasts. To date, 69 TEX genes have been described in different species and different tissues. To evaluate the expression of each TEX/tex gene, we compiled data from 7 different RNA-Seq mRNA databases in humans, and 4 in the mouse according to the expression atlas database. Various studies have highlighted a role for many of these genes in spermatogenesis. Here, we review current knowledge on the TEX genes and their roles in spermatogenesis and fertilization in humans and, comparatively, in other species (notably the mouse). As expected, TEX genes appear to have a major role in reproduction in general and in spermatogenesis in humans but also in all mammals such as the mouse. Most of them are expressed specifically or predominantly in the testis. -
Genetic and Genomic Analysis of Hyperlipidemia, Obesity and Diabetes Using (C57BL/6J × TALLYHO/Jngj) F2 Mice
University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Nutrition Publications and Other Works Nutrition 12-19-2010 Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P. Stewart Marshall University Hyoung Y. Kim University of Tennessee - Knoxville, [email protected] Arnold M. Saxton University of Tennessee - Knoxville, [email protected] Jung H. Kim Marshall University Follow this and additional works at: https://trace.tennessee.edu/utk_nutrpubs Part of the Animal Sciences Commons, and the Nutrition Commons Recommended Citation BMC Genomics 2010, 11:713 doi:10.1186/1471-2164-11-713 This Article is brought to you for free and open access by the Nutrition at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Nutrition Publications and Other Works by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. Stewart et al. BMC Genomics 2010, 11:713 http://www.biomedcentral.com/1471-2164/11/713 RESEARCH ARTICLE Open Access Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P Stewart1, Hyoung Yon Kim2, Arnold M Saxton3, Jung Han Kim1* Abstract Background: Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/ JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia. -
Intrinsic Disorder in PTEN and Its Interactome Confers Structural Plasticity and 63
OPEN Intrinsic Disorder in PTEN and its SUBJECT AREAS: Interactome Confers Structural Plasticity CELLULAR SIGNALLING NETWORKS and Functional Versatility CANCER GENOMICS Prerna Malaney1*, Ravi Ramesh Pathak1*, Bin Xue3, Vladimir N. Uversky3,4,5 & Vrushank Dave´1,2 SYSTEMS ANALYSIS GENE REGULATORY NETWORKS 1Morsani College of Medicine, Department of Pathology and Cell Biology, 2Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, 3Department of Molecular Medicine, 4USF Health Byrd Alzheimer’s Research Institute, Received University of South Florida, Tampa, FL, 33612, USA, 5Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 11 March 2013 Pushchino, Moscow Region, Russia. Accepted 3 June 2013 IDPs, while structurally poor, are functionally rich by virtue of their flexibility and modularity. However, how mutations in IDPs elicit diseases, remain elusive. Herein, we have identified tumor suppressor PTEN as Published an intrinsically disordered protein (IDP) and elucidated the molecular principles by which its intrinsically 20 June 2013 disordered region (IDR) at the carboxyl-terminus (C-tail) executes its functions. Post-translational modifications, conserved eukaryotic linear motifs and molecular recognition features present in the C-tail IDR enhance PTEN’s protein-protein interactions that are required for its myriad cellular functions. PTEN primary and secondary interactomes are also enriched in IDPs, most being cancer related, revealing that Correspondence and PTEN functions emanate from and are nucleated by the C-tail IDR, which form pliable network-hubs. requests for materials Together, PTEN higher order functional networks operate via multiple IDP-IDP interactions facilitated by should be addressed to its C-tail IDR. Targeting PTEN IDR and its interaction hubs emerges as a new paradigm for treatment of V.D. -
WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US). -
Irregular Telomeres Impair Meiotic Synapsis and Recombination in Mice
Irregular telomeres impair meiotic synapsis and recombination in mice Lin Liu*†, Sonia Franco‡, Barbara Spyropoulos§, Peter B. Moens§, Maria A. Blasco‡, and David L. Keefe*†¶ *Department of Obstetrics and Gynecology, Brown Medical School, Women and Infants Hospital, Providence, RI 02905; †Laboratory for Reproductive Medicine, Marine Biological Laboratory, Woods Hole, MA 02543; ‡Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, 28029 Madrid, Spain; and §Department of Biology, York University, North York, ON, Canada M3J 1P3 Edited by Mary-Lou Pardue, Massachusetts Institute of Technology, Cambridge, MA, and approved March 10, 2004 (received for review February 2, 2004) Telomere shortening can lead to chromosome instability, replica- central element at pachytene stage of meiotic prophase I (19– tive senescence, and apoptosis in both somatic and male germ cells. 22). Thus, the structure and number of SCP3 elements provide To study roles for mammalian telomeres in homologous pairing a key marker for evaluating synapsis between homologues. We and recombination, we characterized effects of telomere shorten- analyzed effects of telomere shortening in late-generation ing on spermatogenesis and oogenesis in late-generation telo- TRϪ/Ϫ female mice on meiotic chromosome synapsis and re- merase-deficient mice. We show that shortened telomeres of combination and compared them with males. Because very Ϫ/Ϫ late-generation telomerase-deficient mice impair meiotic synapsis late-generation (G6 or G7)TR male mice exhibit extensive and decrease recombination, in particular, in females. In response apoptosis in germ cells and sterility, we focused on intermediate Ϫ/Ϫ to telomere shortening, male germ cells mostly undergo apoptosis, generation (e.g., G4)TR mice, because these mice show whereas female germ cells preferentially arrest in early meiosis, telomere shortening, but less apoptosis and decreased fertility suggesting sexually dimorphic surveillance mechanisms for telo- (3, 14). -
TEX15 Associates with MILI and Silences Transposable Elements in Male Germ Cells
Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION noncatalytic germ cell-specific paralog of DNMT3A/3B, TEX15 associates with MILI causes reactivation of TEs in male germ cells and loss and silences transposable of maternal genomic imprints, resulting in sterility (Bourc’his et al. 2001; Bourc’his and Bestor 2004). Loss of elements in male germ cells DNMT3C, a rodent and germ cell-specific de novo DNA methyltransferase, leads to reactivation of LINE1 and Fang Yang,1 Yemin Lan,2 Radha Raman Pandey,3 3 2 IAP retrotransposons (Barau et al. 2016). In addition to David Homolka, Shelley L. Berger, DNA methylation, repressive histone modifications Ramesh S. Pillai,3 Marisa S. Bartolomei,2 (H3K9me2 and H3K9me3) are important for silencing of and P. Jeremy Wang1 transposable elements (Di Giacomo et al. 2013; Liu et al. 2014; Pezic et al. 2014; Zamudio et al. 2015). 1Department of Biomedical Sciences, University of Pennsylvania The piRNA (Piwi-associated small noncoding RNAs) School of Veterinary Medicine, Philadelphia, Pennsylvania pathway is an evolutionarily conserved RNA-based TE si- 19104, USA; 2Epigenetics Institute, Department of Cell and lencing mechanism in the germline (Siomi et al. 2011). Developmental Biology, Perelman School of Medicine, piRNAs are mostly derived from TEs in early germ cells University of Pennsylvania, Philadelphia, Pennsylvania 19104, (Aravin et al. 2008; Kuramochi-Miyagawa et al. 2010). Ge- USA; 3Department of Molecular Biology, Science III, University nome-wide demethylation in primordial germ cells of Geneva, CH-1211 Geneva 4, Switzerland (PGCs) causes a burst of TE expression (Bourc’his and Bes- tor 2004). -
Dissertation Meiotic Recombination and Synapsis
DISSERTATION MEIOTIC RECOMBINATION AND SYNAPSIS IN WILD-TYPE AND ASYNAPTIC MUTANTS OF TOMATO (SOLANUM LYCOPERSICUM) Submitted by Huanyu Qiao Department of Biology In partial fulfillment of the requirements For the Degree of Doctor of Philosophy Colorado State University Fort Collins, Colorado Fall 2010 Doctoral Committee: Department Chair: Daniel Bush Advisor: Lorinda Anderson Co-advisor: Stephen Stack Pat Bedinger Rajinder Ranu ABSTRACT MEIOTIC RECOMBINATION AND SYNAPSIS IN WILD-TYPE AND ASYNAPTIC MUTANTS OF TOMATO (SOLANUM LYCOPERSICUM) Recombination nodules (RNs) and synaptonemal complexes (SCs) are meiosis-specific structures that play important roles in crossing over. During pachytene, RNs mark crossover sites along SCs. MLH1, a mismatch repair protein, promotes crossing over and is a component of most RNs. In wild-type tomato, each bivalent has one, two or three crossovers (=chiasmata), and the number and distribution of these crossovers is affected by crossover interference (the tendency for one crossover to reduce the likelihood of another crossover nearby). Although the phenomenon of genetic interference was discovered nearly one hundred years ago, its molecular basis is still unknown. SCs occur between pairs of homologous chromosomes (bivalents) during prophase I and consist of two parallel rod-like lateral elements held together by transverse fibers. Each lateral element is associated with the two sister chromatids of one of the homologous chromosomes. Cohesin complexes consisting of four proteins (SMC1, SMC3, SYN1/REC8 and SCC3) are found in lateral elements and link sister chromatids together. My research addressed the question of how synapsis (SC formation) is related to the frequency and control of crossing over using tomato, particularly the as1 meiotic mutant, as a model system. -
Expression Analysis of Genes Encoding TEX11, TEX12, TEX14 and TEX15 in Testis Tissues of Men with Non-Obstructive Azoospermia
JBRA Assisted Reproduction 2018;00(0):000-000 doi: 10.5935/1518-0557.20180030 Original article Expression analysis of genes encoding TEX11, TEX12, TEX14 and TEX15 in testis tissues of men with non-obstructive azoospermia Parnaz Borjian Boroujeni1, Marjan Sabbaghian2, Mehdi Totonchi1,3, Niloofar Sodeifi2, Homa Sarkardeh1, Azam Samadian3, Mohammad Ali Sadighi-Gilani2,4, Hamid Gourabi1 1Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran 2Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran 3Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran 4Department of Urology, Shariati Hospital, Tehran University of Medical Science, Tehran, Iran Congresses where the study was presented: Middle East Fertility Society (MEFS) congress 2012, 2013 Royan International Twin Congress 2013, 2014 ABSTRACT Previous studies have revealed that TEX11, TEX12, Objective: Spermatogenesis is a complex process con- TEX14 and TEX15 expression is restricted to germ cells trolled by a plethora of genes. Changes in expression and and is not detectable in somatic tissues of humans and function of these genes may thus lead to spermatogenic mice (Wang et al., 2001; Adelman & Petrini, 2008). Mul- deficiency and male infertility. TEX11, TEX12, TEX14 and tiple studies have shown that X-linked germ cell-specif- TEX15 are germ cell-specific genes expressed in the tes- ic genes such as testis-expressed gene 11 (Tex11) have tis. TEX11, involved in the initiation and maintenance of significant roles in regulating male fertility (Zheng et al., chromosome synapses in meiotic chromosomes, has been 2010; Matzuk & Lamb, 2008). -
Aberrant Recombination and Repair During Immunoglobulin Class Switching in BRCA1-Deficient Human B Cells
Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells Andrea Björkmana, Per Qvistb,c, Likun Dua, Margarita Bartisha, Apostolos Zaravinosa, Konstantinos Georgioua, Anders D. Børglumb,c, Richard A. Gattid,e, Therese Törngrenf, and Qiang Pan-Hammarströma,1 aDepartment of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden; bDepartment of Biomedicine and cCentre for Integrative Sequencing, Aarhus University, 8000 Aarhus, Denmark; Departments of dPathology and Laboratory Medicine and eHuman Genetics, University of California, Los Angeles, CA 90095; and fDivision of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund 22100, Sweden Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, Canada, and approved January 7, 2015 (received for review October 3, 2014) Breast cancer type 1 susceptibility protein (BRCA1) has a multitude (1). When the c-NHEJ pathway is defective, alternative end- of functions that contribute to genome integrity and tumor sup- joining (A-EJ) pathway(s), often associated with resections/dele- pression. Its participation in the repair of DNA double-strand tions and longer MHs, may be operating (1–3). breaks (DSBs) during homologous recombination (HR) is well rec- DSBs are not always pathological, but can also be interme- ognized, whereas its involvement in the second major DSB repair diates of physiological processes, such as those that occur during pathway, nonhomologous end-joining (NHEJ), remains controver- B-cell development. Then, extensive gene rearrangements/mod- sial. Here we have studied the role of BRCA1 in the repair of ifications at the Ig gene loci may occur, resulting in production of DSBs in switch (S) regions during immunoglobulin class switch re- functional antibodies that can recognize and act against an im- combination, a physiological, deletion/recombination process that mense number of different pathogens. -
The Male Germline-Specific Protein MAPS Is Indispensable for Pachynema Progression and Fertility
The male germline-specific protein MAPS is indispensable for pachynema progression and fertility Miao Lia,b, Jiahuan Zhenga,b, Gaopeng Lic, Zexiong Lina, Dongliang Lia, Dongteng Liua,b, Haiwei Fenga,b, Dandan Caoa, Ernest H. Y. Nga,b, Raymond H. W. Lia,b, Chunsheng Hand,e,f, William S. B. Yeunga,b, Louise T. Chowc,1, Hengbin Wangc,1, and Kui Liua,b,1 aShenzhen Key Laboratory of Fertility Regulation, Center of Assisted Reproduction and Embryology, The University of Hong Kong–Shenzhen Hospital, 518053 Shenzhen, Guangdong, China; bDepartment of Obstetrics and Gynecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; cDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024; dState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China; eInstitute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101 Beijing, China; and fUniversity of Chinese Academy of Sciences, Chinese Academy of Sciences, 100049 Beijing, China Contributed by Louise T. Chow, January 12, 2021 (sent for review December 10, 2020; reviewed by Anders Hofer, Kazuhiro Kawamura, and Mingxi Liu) Meiosis is a specialized cell division that creates haploid germ cells to transient transcriptional silencing in a process termed meiotic from diploid progenitors. Through differential RNA expression sex chromosome inactivation (MSCI) (6, 7). analyses, we previously identified a number of mouse genes that Over the past decades, the underlying molecular aspects of were dramatically elevated in spermatocytes, relative to their very meiosis prophase I have been widely studied. Various mutant low expression in spermatogonia and somatic organs.