TY - JOUR A1 - Dunce, James M. A1 - Milburn, Amy E. A1 - Gurusaran, Manickam A1 - da Cruz, Irene A1 - Sen, Lee T. A1 - Benavente, Ricardo A1 - Davies, Owen R. T1 - Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1 JF - Nature Communications N2 - Meiotic chromosomes undergo rapid prophase movements, which are thought to facilitate the formation of inter-homologue recombination intermediates that underlie synapsis, crossing over and segregation. The meiotic telomere complex (MAJIN, TERB1, TERB2) tethers telomere ends to the nuclear envelope and transmits cytoskeletal forces via the LINC complex to drive these rapid movements. Here, we report the molecular architecture of the meiotic telomere complex through the crystal structure of MAJIN-TERB2, together with light and X-ray scattering studies of wider complexes. The MAJIN-TERB2 2:2 hetero-tetramer binds strongly to DNA and is tethered through long flexible linkers to the inner nuclear membrane and two TRF1-binding 1:1 TERB2-TERB1 complexes. Our complementary structured illumination microscopy studies and biochemical findings reveal a telomere attachment mechanism in which MAJIN-TERB2-TERB1 recruits telomere-bound TRF1, which is then displaced during pachytene, allowing MAJIN-TERB2-TERB1 to bind telomeric DNA and form a mature attachment plate. KW - DNA KW - meiosis KW - proteins KW - super-resolution microscopy KW - X-ray crystallography Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226416 VL - 9 ER - TY - JOUR A1 - Bencurova, Elena A1 - Akash, Aman A1 - Dobson, Renwick C.J. A1 - Dandekar, Thomas T1 - DNA storage-from natural biology to synthetic biology JF - Computational and Structural Biotechnology Journal N2 - Natural DNA storage allows cellular differentiation, evolution, the growth of our children and controls all our ecosystems. Here, we discuss the fundamental aspects of DNA storage and recent advances in this field, with special emphasis on natural processes and solutions that can be exploited. We point out new ways of efficient DNA and nucleotide storage that are inspired by nature. Within a few years DNA-based information storage may become an attractive and natural complementation to current electronic data storage systems. We discuss rapid and directed access (e.g. DNA elements such as promotors, enhancers), regulatory signals and modulation (e.g. lncRNA) as well as integrated high-density storage and processing modules (e.g. chromosomal territories). There is pragmatic DNA storage for use in biotechnology and human genetics. We examine DNA storage as an approach for synthetic biology (e.g. light-controlled nucleotide processing enzymes). The natural polymers of DNA and RNA offer much for direct storage operations (read-in, read-out, access control). The inbuilt parallelism (many molecules at many places working at the same time) is important for fast processing of information. Using biology concepts from chromosomal storage, nucleic acid processing as well as polymer material sciences such as electronical effects in enzymes, graphene, nanocellulose up to DNA macramé , DNA wires and DNA-based aptamer field effect transistors will open up new applications gradually replacing classical information storage methods in ever more areas over time (decades). KW - DNA KW - RNA KW - data storage KW - natural processing KW - synthetic biology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-349971 SN - 2001-0370 VL - 21 ER - TY - JOUR A1 - Neitz, Hermann A1 - Bessi, Irene A1 - Kachler, Valentin A1 - Michel, Manuela A1 - Höbartner, Claudia T1 - Tailored tolane‐perfluorotolane assembly as supramolecular base pair replacement in DNA JF - Angewandte Chemie International Edition N2 - Arene‐fluoroarene interactions offer outstanding possibilities for engineering of supramolecular systems, including nucleic acids. Here, we implement the tolane‐perfluorotolane interaction as base pair replacement in DNA. Tolane (THH) and perfluorotolane (TFF) moieties were connected to acyclic backbone units, comprising glycol nucleic acid (GNA) or butyl nucleic acid (BuNA) building blocks, that were incorporated via phosphoramidite chemistry at opposite positions in a DNA duplex. Thermodynamic analyses by UV thermal melting revealed a compelling stabilization by THH/TFF heteropairs only when connected to the BuNA backbone, but not with the shorter GNA linker. Detailed NMR studies confirmed the preference of the BuNA backbone for enhanced polar π‐stacking. This work defines how orthogonal supramolecular interactions can be tailored by small constitutional changes in the DNA backbone, and it inspires future studies of arene‐fluoroarene‐programmed assembly of DNA. KW - arene-fluoroarene KW - artificial base pair KW - DNA KW - sSupramolecular interaction KW - XNA Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312575 VL - 62 IS - 1 ER - TY - JOUR A1 - Aydinli, Muharrem A1 - Liang, Chunguang A1 - Dandekar, Thomas T1 - Motif and conserved module analysis in DNA (promoters, enhancers) and RNA (lncRNA, mRNA) using AlModules JF - Scientific Reports N2 - Nucleic acid motifs consist of conserved and variable nucleotide regions. For functional action, several motifs are combined to modules. The tool AIModules allows identification of such motifs including combinations of them and conservation in several nucleic acid stretches. AIModules recognizes conserved motifs and combinations of motifs (modules) allowing a number of interesting biological applications such as analysis of promoter and transcription factor binding sites (TFBS), identification of conserved modules shared between several gene families, e.g. promoter regions, but also analysis of shared and conserved other DNA motifs such as enhancers and silencers, in mRNA (motifs or regulatory elements e.g. for polyadenylation) and lncRNAs. The tool AIModules presented here is an integrated solution for motif analysis, offered as a Web service as well as downloadable software. Several nucleotide sequences are queried for TFBSs using predefined matrices from the JASPAR DB or by using one’s own matrices for diverse types of DNA or RNA motif discovery. Furthermore, AIModules can find TFBSs common to two or more sequences. Demanding high or low conservation, AIModules outperforms other solutions in speed and finds more modules (specific combinations of TFBS) than alternative available software. The application also searches RNA motifs such as polyadenylation site or RNA–protein binding motifs as well as DNA motifs such as enhancers as well as user-specified motif combinations (https://bioinfo-wuerz.de/aimodules/; alternative entry pages: https://aimodules.heinzelab.de or https://www.biozentrum.uni-wuerzburg.de/bioinfo/computing/aimodules). The application is free and open source whether used online, on-site, or locally. KW - AIModules KW - nucleic acid motifs KW - DNA Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301268 VL - 12 IS - 1 ER - TY - JOUR A1 - Sanyal, Anirban A1 - Wallaschek, Nina A1 - Glass, Mandy A1 - Flamand, Louis A1 - Wight, Darren J. A1 - Kaufer, Benedikt B. T1 - The ND10 Complex Represses Lytic Human Herpesvirus 6A Replication and Promotes Silencing of the Viral Genome JF - Viruses N2 - Human herpesvirus 6A (HHV-6A) replicates in peripheral blood mononuclear cells (PBMCs) and various T-cell lines in vitro. Intriguingly, the virus can also establish latency in these cells, but it remains unknown what influences the decision between lytic replication and the latency of the virus. Incoming virus genomes are confronted with the nuclear domain 10 (ND10) complex as part of an intrinsic antiviral response. Most herpesviruses can efficiently subvert ND10, but its role in HHV-6A infection remains poorly understood. In this study, we investigated if the ND10 complex affects HHV-6A replication and contributes to the silencing of the virus genome during latency. We could demonstrate that ND10 complex was not dissociated upon infection, while the number of ND10 bodies was reduced in lytically infected cells. Virus replication was significantly enhanced upon knock down of the ND10 complex using shRNAs against its major constituents promyelocytic leukemia protein (PML), hDaxx, and Sp100. In addition, we could demonstrate that viral genes are more efficiently silenced in the presence of a functional ND10 complex. Our data thereby provides the first evidence that the cellular ND10 complex plays an important role in suppressing HHV-6A lytic replication and the silencing of the virus genome in latently infected cells. KW - human herpesvirus 6 KW - ND10 complex KW - PML KW - lytic replication KW - latency KW - PML nuclear-bodies KW - gene-expression KW - virus-infection KW - in-vitro KW - DNA Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227337 VL - 10 IS - 8 ER - TY - JOUR A1 - Reynolds, David L. A1 - Hofmeister, Brigitte T. A1 - Cliffe, Laura A1 - Siegel, T. Nicolai A1 - Andersson, Britta A. A1 - Beverley, Stephen M. A1 - Schmitz, Robert J. A1 - Sabatini, Robert T1 - Base J represses genes at the end of polycistronic gene clusters in Leishmania major by promoting RNAP II termination JF - Molecular Microbiology N2 - The genomes of kinetoplastids are organized into polycistronic gene clusters that are flanked by the modified DNA base J. Previous work has established a role of base J in promoting RNA polymerase II termination in Leishmania spp. where the loss of J leads to termination defects and transcription into adjacent gene clusters. It remains unclear whether these termination defects affect gene expression and whether read through transcription is detrimental to cell growth, thus explaining the essential nature of J. We now demonstrate that reduction of base J at specific sites within polycistronic gene clusters in L. major leads to read through transcription and increased expression of downstream genes in the cluster. Interestingly, subsequent transcription into the opposing polycistronic gene cluster does not lead to downregulation of sense mRNAs. These findings indicate a conserved role for J regulating transcription termination and expression of genes within polycistronic gene clusters in trypanosomatids. In contrast to the expectations often attributed to opposing transcription, the essential nature of J in Leishmania spp. is related to its role in gene repression rather than preventing transcriptional interference resulting from read through and dual strand transcription. KW - Trypanosoma-brucei KW - Transcription initiation KW - Messenger RNA KW - DNA KW - Genome KW - Cruzi KW - Hydroxymethyluracil KW - Expression KW - Parasite KW - Glucosyltransferase Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187727 VL - 101 IS - 4 ER - TY - JOUR A1 - Ziegler, C. A1 - Richter, J. A1 - Mahr, M. A1 - Gajewska, A. A1 - Schiele, M.A. A1 - Gehrmann, A. A1 - Schmidt, B. A1 - Lesch, K.-P. A1 - Lang, T. A1 - Helbig-Lang, S. A1 - Pauli, P. A1 - Kircher, T. A1 - Reif, A. A1 - Rief, W. A1 - Vossbeck-Elsebusch, A.N. A1 - Arolt, V. A1 - Wittchen, H.-U. A1 - Hamm, A.O. A1 - Deckert, J. A1 - Domschke, K. T1 - MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy JF - Translational Psychiatry N2 - Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17%), while non-responders further decreased in methylation (-2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects. KW - Adult KW - Case-Control Studies KW - Cognitive Therapy KW - DNA Methylation KW - Epigenesis KW - Genetic KW - Female KW - Humans KW - Monoamine Oxidase/genetics KW - Panic Disorder/genetics KW - Panic Disorder/therapy KW - Sequence Analysis KW - DNA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164422 IS - 6 ER - TY - JOUR A1 - Cui, Huanhuan A1 - Schlesinger, Jenny A1 - Schoenhals, Sophia A1 - Tonjes, Martje A1 - Dunkel, Ilona A1 - Meierhofer, David A1 - Cano, Elena A1 - Schulz, Kerstin A1 - Berger, Michael F. A1 - Haack, Timm A1 - Abdelilah-Seyfried, Salim A1 - Bulyk, Martha L. A1 - Sauer, Sascha A1 - Sperling, Silke R. T1 - Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA JF - Nucleic Acids Research N2 - DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure. KW - phosphorylation KW - DPF3a KW - HEY repressors KW - DNA KW - cardiac hypertrophy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166391 VL - 44 IS - 6 ER - TY - JOUR A1 - Buchheim, Mark A. A1 - Keller, Alexander A1 - Koetschan, Christian A1 - Förster, Frank A1 - Merget, Benjamin A1 - Wolf, Matthias T1 - Internal Transcribed Spacer 2 (nu ITS2 rRNA) Sequence-Structure Phylogenetics: Towards an Automated Reconstruction of the Green Algal Tree of Life JF - PLoS ONE N2 - Background: Chloroplast-encoded genes (matK and rbcL) have been formally proposed for use in DNA barcoding efforts targeting embryophytes. Extending such a protocol to chlorophytan green algae, though, is fraught with problems including non homology (matK) and heterogeneity that prevents the creation of a universal PCR toolkit (rbcL). Some have advocated the use of the nuclear-encoded, internal transcribed spacer two (ITS2) as an alternative to the traditional chloroplast markers. However, the ITS2 is broadly perceived to be insufficiently conserved or to be confounded by introgression or biparental inheritance patterns, precluding its broad use in phylogenetic reconstruction or as a DNA barcode. A growing body of evidence has shown that simultaneous analysis of nucleotide data with secondary structure information can overcome at least some of the limitations of ITS2. The goal of this investigation was to assess the feasibility of an automated, sequence-structure approach for analysis of IT2 data from a large sampling of phylum Chlorophyta. Methodology/Principal Findings: Sequences and secondary structures from 591 chlorophycean, 741 trebouxiophycean and 938 ulvophycean algae, all obtained from the ITS2 Database, were aligned using a sequence structure-specific scoring matrix. Phylogenetic relationships were reconstructed by Profile Neighbor-Joining coupled with a sequence structure-specific, general time reversible substitution model. Results from analyses of the ITS2 data were robust at multiple nodes and showed considerable congruence with results from published phylogenetic analyses. Conclusions/Significance: Our observations on the power of automated, sequence-structure analyses of ITS2 to reconstruct phylum-level phylogenies of the green algae validate this approach to assessing diversity for large sets of chlorophytan taxa. Moreover, our results indicate that objections to the use of ITS2 for DNA barcoding should be weighed against the utility of an automated, data analysis approach with demonstrated power to reconstruct evolutionary patterns for highly divergent lineages. KW - RBCL Gene-sequences KW - Colonial volvocales chlorophyta KW - 26S RDNA Data KW - Land plants KW - Molecular systematics KW - Secondary structure KW - Nuclear RDNA KW - DNA KW - Barcodes KW - Dasycladales chlorophyta KW - Profile distances Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140866 VL - 6 IS - 2 ER - TY - JOUR A1 - Blein, Sophie A1 - Bardel, Claire A1 - Danjean, Vincent A1 - McGuffog, Lesley A1 - Healay, Sue A1 - Barrowdale, Daniel A1 - Lee, Andrew A1 - Dennis, Joe A1 - Kuchenbaecker, Karoline B. A1 - Soucy, Penny A1 - Terry, Mary Beth A1 - Chung, Wendy K. A1 - Goldgar, David E. A1 - Buys, Saundra S. A1 - Janavicius, Ramunas A1 - Tihomirova, Laima A1 - Tung, Nadine A1 - Dorfling, Cecilia M. A1 - van Rensburg, Elizabeth J. A1 - Neuhausen, Susan L. A1 - Ding, Yuan Chun A1 - Gerdes, Anne-Marie A1 - Ejlertsen, Bent A1 - Nielsen, Finn C. A1 - Hansen, Thomas V. O. A1 - Osorio, Ana A1 - Benitez, Javier A1 - Andreas Conejero, Raquel A1 - Segota, Ena A1 - Weitzel, Jeffrey N. A1 - Thelander, Margo A1 - Peterlongo, Paolo A1 - Radice, Paolo A1 - Pensotti, Valeria A1 - Dolcetti, Riccardo A1 - Bonanni, Bernardo A1 - Peissel, Bernard A1 - Zaffaroni, Daniela A1 - Scuvera, Giulietta A1 - Manoukian, Siranoush A1 - Varesco, Liliana A1 - Capone, Gabriele L. A1 - Papi, Laura A1 - Ottini, Laura A1 - Yannoukakos, Drakoulis A1 - Konstantopoulou, Irene A1 - Garber, Judy A1 - Hamann, Ute A1 - Donaldson, Alan A1 - Brady, Angela A1 - Brewer, Carole A1 - Foo, Claire A1 - Evans, D. Gareth A1 - Frost, Debra A1 - Eccles, Diana A1 - Douglas, Fiona A1 - Cook, Jackie A1 - Adlard, Julian A1 - Barwell, Julian A1 - Walker, Lisa A1 - Izatt, Louise A1 - Side, Lucy E. A1 - Kennedy, M. John A1 - Tischkowitz, Marc A1 - Rogers, Mark T. A1 - Porteous, Mary E. A1 - Morrison, Patrick J. A1 - Platte, Radka A1 - Eeles, Ros A1 - Davidson, Rosemarie A1 - Hodgson, Shirley A1 - Cole, Trevor A1 - Godwin, Andrew K A1 - Isaacs, Claudine A1 - Claes, Kathleen A1 - De Leeneer, Kim A1 - Meindl, Alfons A1 - Gehrig, Andrea A1 - Wappenschmidt, Barbara A1 - Sutter, Christian A1 - Engel, Christoph A1 - Niederacher, Dieter A1 - Steinemann, Doris A1 - Plendl, Hansjoerg A1 - Kast, Karin A1 - Rhiem, Kerstin A1 - Ditsch, Nina A1 - Arnold, Norbert A1 - Varon-Mateeva, Raymonda A1 - Schmutzler, Rita K. A1 - Preisler-Adams, Sabine A1 - Markov, Nadja Bogdanova A1 - Wang-Gohrke, Shan A1 - de Pauw, Antoine A1 - Lefol, Cedrick A1 - Lasset, Christine A1 - Leroux, Dominique A1 - Rouleau, Etienne A1 - Damiola, Francesca A1 - Dreyfus, Helene A1 - Barjhoux, Laure A1 - Golmard, Lisa A1 - Uhrhammer, Nancy A1 - Bonadona, Valerie A1 - Sornin, Valerie A1 - Bignon, Yves-Jean A1 - Carter, Jonathan A1 - Van Le, Linda A1 - Piedmonte, Marion A1 - DiSilvestro, Paul A. A1 - de la Hoya, Miguel A1 - Caldes, Trinidad A1 - Nevanlinna, Heli A1 - Aittomäki, Kristiina A1 - Jager, Agnes A1 - van den Ouweland, Ans M. W. A1 - Kets, Carolien M. A1 - Aalfs, Cora M. A1 - van Leeuwen, Flora E. A1 - Hogervorst, Frans B. L. A1 - Meijers-Heijboer, Hanne E. J. A1 - Oosterwijk, Jan C. A1 - van Roozendaal, Kees E. P. A1 - Rookus, Matti A. A1 - Devilee, Peter A1 - van der Luijt, Rob B. A1 - Olah, Edith A1 - Diez, Orland A1 - Teule, Alex A1 - Lazaro, Conxi A1 - Blanco, Ignacio A1 - Del Valle, Jesus A1 - Jakubowska, Anna A1 - Sukiennicki, Grzegorz A1 - Gronwald, Jacek A1 - Spurdle, Amanda B. A1 - Foulkes, William A1 - Olswold, Curtis A1 - Lindor, Noralene M. A1 - Pankratz, Vernon S. A1 - Szabo, Csilla I. A1 - Lincoln, Anne A1 - Jacobs, Lauren A1 - Corines, Marina A1 - Robson, Mark A1 - Vijai, Joseph A1 - Berger, Andreas A1 - Fink-Retter, Anneliese A1 - Singer, Christian F. A1 - Rappaport, Christine A1 - Geschwantler Kaulich, Daphne A1 - Pfeiler, Georg A1 - Tea, Muy-Kheng A1 - Greene, Mark H. A1 - Mai, Phuong L. A1 - Rennert, Gad A1 - Imyanitov, Evgeny N. A1 - Mulligan, Anna Marie A1 - Glendon, Gord A1 - Andrulis, Irene L. A1 - Tchatchou, Andrine A1 - Toland, Amanda Ewart A1 - Pedersen, Inge Sokilde A1 - Thomassen, Mads A1 - Kruse, Torben A. A1 - Jensen, Uffe Birk A1 - Caligo, Maria A. A1 - Friedman, Eitan A1 - Zidan, Jamal A1 - Laitman, Yael A1 - Lindblom, Annika A1 - Melin, Beatrice A1 - Arver, Brita A1 - Loman, Niklas A1 - Rosenquist, Richard A1 - Olopade, Olufunmilayo I. A1 - Nussbaum, Robert L. A1 - Ramus, Susan J. A1 - Nathanson, Katherine L. A1 - Domchek, Susan M. A1 - Rebbeck, Timothy R. A1 - Arun, Banu K. A1 - Mitchell, Gillian A1 - Karlan, Bethy Y. A1 - Lester, Jenny A1 - Orsulic, Sandra A1 - Stoppa-Lyonnet, Dominique A1 - Thomas, Gilles A1 - Simard, Jacques A1 - Couch, Fergus J. A1 - Offit, Kenenth A1 - Easton, Douglas F. A1 - Chenevix-Trench, Georgia A1 - Antoniou, Antonis C. A1 - Mazoyer, Sylvie A1 - Phelan, Catherine M. A1 - Sinilnikova, Olga M. A1 - Cox, David G. T1 - An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers JF - Breast Cancer Research N2 - Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects. KW - single-nucleotide polymorphisms KW - genetic modifiers KW - oxidative stress KW - consortium KW - multiple diseases KW - DNA KW - haplogroups KW - susceptibility KW - Ovarian KW - variants Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145458 VL - 17 IS - 61 ER -