A Process of Resection-Dependent Nonhomologous End
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RB Localizes to DNA Double-Strand Breaks and Promotes DNA End Resection and Homologous Recombination Through the Recruitment of BRG1
Downloaded from genesdev.cshlp.org on October 9, 2021 - Published by Cold Spring Harbor Laboratory Press RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1 Renier Vélez-Cruz,1 Swarnalatha Manickavinayaham,1 Anup K. Biswas,1,3 Regina Weaks Clary,1,2 Tolkappiyan Premkumar,1,2 Francesca Cole,1,2 and David G. Johnson1,2 1Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville Texas 78957, USA; 2The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77225, USA The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double-strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome insta- bility. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1, and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability, and renders mice hypersensitive to IR. Importantly, depletion of RB in osteosarcoma and breast cancer cell lines results in sensitivity to DNA-damaging drugs, which is further exacerbated by poly-ADP ribose polymerase (PARP) inhibitors. -
DNA Damage Induced During Mitosis Undergoes DNA Repair
bioRxiv preprint doi: https://doi.org/10.1101/2020.01.03.893784; this version posted January 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 DNA damage induced during mitosis 2 undergoes DNA repair synthesis 3 4 5 Veronica Gomez Godinez1 ,Sami Kabbara2,3,1a, Adria Sherman1,3, Tao Wu3,4, 6 Shirli Cohen1, Xiangduo Kong5, Jose Luis Maravillas-Montero6,1b, Zhixia Shi1, 7 Daryl Preece,4,3, Kyoko Yokomori5, Michael W. Berns1,2,3,4* 8 9 1Institute of Engineering in Medicine, University of Ca-San Diego, San Diego, California, United 10 States of America 11 12 2Department of Developmental and Cell Biology, University of Ca-Irvine, Irvine, California, United 13 States of America 14 15 3Beckman Laser Institute, University of Ca-Irvine, Irvine, California, United States of America 16 17 4Department of Biomedical Engineering, University of Ca-Irvine, Irvine, California, United States of 18 America 19 20 5Department of Biological Chemistry, University of Ca-Irvine, Irvine, California, United States of 21 America 22 23 6Department of Physiology, University of Ca-Irvine, Irvine, California, United States of America 24 25 1aCurrent Address: Tulane Department of Opthalmology, New Orleans, Louisiana, United States of 26 America 27 28 1bCurrent Address: Universidad Nacional Autonoma de Mexico, Mexico CDMX, Mexico 29 30 31 32 *Corresponding Author 33 34 [email protected](M.W.B) 35 36 37 38 39 40 41 42 43 44 45 46 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.01.03.893784; this version posted January 3, 2020. -
Phosphatidylinositol-3-Kinase Related Kinases (Pikks) in Radiation-Induced Dna Damage
Mil. Med. Sci. Lett. (Voj. Zdrav. Listy) 2012, vol. 81(4), p. 177-187 ISSN 0372-7025 DOI: 10.31482/mmsl.2012.025 REVIEW ARTICLE PHOSPHATIDYLINOSITOL-3-KINASE RELATED KINASES (PIKKS) IN RADIATION-INDUCED DNA DAMAGE Ales Tichy 1, Kamila Durisova 1, Eva Novotna 1, Lenka Zarybnicka 1, Jirina Vavrova 1, Jaroslav Pejchal 2, Zuzana Sinkorova 1 1 Department of Radiobiology, Faculty of Health Sciences in Hradec Králové, University of Defence in Brno, Czech Republic 2 Centrum of Advanced Studies, Faculty of Health Sciences in Hradec Králové, University of Defence in Brno, Czech Republic. Received 5 th September 2012. Revised 27 th November 2012. Published 7 th December 2012. Summary This review describes a drug target for cancer therapy, family of phosphatidylinositol-3 kinase related kinases (PIKKs), and it gives a comprehensive review of recent information. Besides general information about phosphatidylinositol-3 kinase superfamily, it characterizes a DNA-damage response pathway since it is monitored by PIKKs. Key words: PIKKs; ATM; ATR; DNA-PK; Ionising radiation; DNA-repair ABBREVIATIONS therapy and radiation play a pivotal role. Since cancer is one of the leading causes of death worldwide, it is DSB - double stand breaks, reasonable to invest time and resources in the enligh - IR - ionising radiation, tening of mechanisms, which underlie radio-resis - p53 - TP53 tumour suppressors, tance. PI - phosphatidylinositol. The aim of this review is to describe the family INTRODUCTION of phosphatidyinositol 3-kinases (PI3K) and its func - tional subgroup - phosphatidylinositol-3-kinase rela - An efficient cancer treatment means to restore ted kinases (PIKKs) and their relation to repairing of controlled tissue growth via interfering with cell sig - radiation-induced DNA damage. -
Generation of a Mouse Model Lacking the Non-Homologous End-Joining Factor Mri/Cyren
biomolecules Article Generation of a Mouse Model Lacking the Non-Homologous End-Joining Factor Mri/Cyren 1,2, 1,2, 1,2, 1,2 Sergio Castañeda-Zegarra y , Camilla Huse y, Øystein Røsand y, Antonio Sarno , Mengtan Xing 1,2, Raquel Gago-Fuentes 1,2, Qindong Zhang 1,2, Amin Alirezaylavasani 1,2, Julia Werner 1,2,3, Ping Ji 1, Nina-Beate Liabakk 1, Wei Wang 1, Magnar Bjørås 1,2 and Valentyn Oksenych 1,2,4,* 1 Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway; [email protected] (S.C.-Z.); [email protected] (C.H.); [email protected] (Ø.R.); [email protected] (A.S.); [email protected] (M.X.); [email protected] (R.G.-F.); [email protected] (Q.Z.); [email protected] (A.A.); [email protected] (J.W.); [email protected] (P.J.); [email protected] (N.-B.L.); [email protected] (W.W.); [email protected] (M.B.) 2 St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway 3 Molecular Biotechnology MS programme, Heidelberg University, 69120 Heidelberg, Germany 4 Department of Biosciences and Nutrition (BioNut), Karolinska Institutet, 14183 Huddinge, Sweden * Correspondence: [email protected]; Tel.: +47-913-43-084 These authors contributed equally to this work. y Received: 7 November 2019; Accepted: 26 November 2019; Published: 28 November 2019 Abstract: Classical non-homologous end joining (NHEJ) is a molecular pathway that detects, processes, and ligates DNA double-strand breaks (DSBs) throughout the cell cycle. -
Insights Into Regulation of Human RAD51 Nucleoprotein Filament Activity During
Insights into Regulation of Human RAD51 Nucleoprotein Filament Activity During Homologous Recombination Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Ravindra Bandara Amunugama, B.S. Biophysics Graduate Program The Ohio State University 2011 Dissertation Committee: Richard Fishel PhD, Advisor Jeffrey Parvin MD PhD Charles Bell PhD Michael Poirier PhD Copyright by Ravindra Bandara Amunugama 2011 ABSTRACT Homologous recombination (HR) is a mechanistically conserved pathway that occurs during meiosis and following the formation of DNA double strand breaks (DSBs) induced by exogenous stresses such as ionization radiation. HR is also involved in restoring replication when replication forks have stalled or collapsed. Defective recombination machinery leads to chromosomal instability and predisposition to tumorigenesis. However, unregulated HR repair system also leads to similar outcomes. Fortunately, eukaryotes have evolved elegant HR repair machinery with multiple mediators and regulatory inputs that largely ensures an appropriate outcome. A fundamental step in HR is the homology search and strand exchange catalyzed by the RAD51 recombinase. This process requires the formation of a nucleoprotein filament (NPF) on single-strand DNA (ssDNA). In Chapter 2 of this dissertation I describe work on identification of two residues of human RAD51 (HsRAD51) subunit interface, F129 in the Walker A box and H294 of the L2 ssDNA binding region that are essential residues for salt-induced recombinase activity. Mutation of F129 or H294 leads to loss or reduced DNA induced ATPase activity and formation of a non-functional NPF that eliminates recombinase activity. DNA binding studies indicate that these residues may be essential for sensing the ATP nucleotide for a functional NPF formation. -
A Process of Resection-Dependent Nonhomologous End Joining Involving the Goddess Artemis
A process of resection-dependent nonhomologous end joining involving the goddess Artemis Article (Published Version) Jeggo, Penny and Löbrich, Markus (2017) A process of resection-dependent nonhomologous end joining involving the goddess Artemis. Trends in Biochemical Sciences, 42 (9). pp. 690-701. ISSN 0968-0004 This version is available from Sussex Research Online: http://sro.sussex.ac.uk/id/eprint/77876/ This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the URL above for details on accessing the published version. Copyright and reuse: Sussex Research Online is a digital repository of the research output of the University. Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available. Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. http://sro.sussex.ac.uk [160_TD$IF]Opinion A Process of Resection- Dependent Nonhomologous End Joining Involving the Goddess Artemis Markus Löbrich1,* and Penny Jeggo2,* DNA double-strand breaks (DSBs) are a hazardous form of damage that can Trends potentially cause cell death or genomic rearrangements. -
Error-Prone DNA Repair As Cancer's Achilles' Heel
cancers Review Alternative Non-Homologous End-Joining: Error-Prone DNA Repair as Cancer’s Achilles’ Heel Daniele Caracciolo, Caterina Riillo , Maria Teresa Di Martino , Pierosandro Tagliaferri and Pierfrancesco Tassone * Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, 88100 Catanzaro, Italy; [email protected] (D.C.); [email protected] (C.R.); [email protected] (M.T.D.M.); [email protected] (P.T.) * Correspondence: [email protected] Simple Summary: Cancer onset and progression lead to a high rate of DNA damage, due to replicative and metabolic stress. To survive in this dangerous condition, cancer cells switch the DNA repair machinery from faithful systems to error-prone pathways, strongly increasing the mutational rate that, in turn, supports the disease progression and drug resistance. Although DNA repair de-regulation boosts genomic instability, it represents, at the same time, a critical cancer vulnerability that can be exploited for synthetic lethality-based therapeutic intervention. We here discuss the role of the error-prone DNA repair, named Alternative Non-Homologous End Joining (Alt-NHEJ), as inducer of genomic instability and as a potential therapeutic target. We portray different strategies to drug Alt-NHEJ and discuss future challenges for selecting patients who could benefit from Alt-NHEJ inhibition, with the aim of precision oncology. Abstract: Error-prone DNA repair pathways promote genomic instability which leads to the onset of cancer hallmarks by progressive genetic aberrations in tumor cells. The molecular mechanisms which Citation: Caracciolo, D.; Riillo, C.; Di foster this process remain mostly undefined, and breakthrough advancements are eagerly awaited. Martino, M.T.; Tagliaferri, P.; Tassone, In this context, the alternative non-homologous end joining (Alt-NHEJ) pathway is considered P. -
Radiation-Sensitive Severe Combined Immunodeficiency (RS-SCID)
Radiation-sensitive severe combined immunodeficiency (RS-SCID) Contact details Introduction Molecular Genetics Service Severe combined immunodeficiency (SCID) is a group of genetically and Level 6, York House phenotypically heterogeneous disorders that can be immunologically classified by the 37 Queen Square absence or presence of T, B, and natural killer (NK) cells. The most severe form of - - + London, WC1N 3BH SCID has the T B NK phenotype, accounting for ~20% of all cases in which patients T +44 (0) 20 7762 6888 present with a virtual absence of both circulating T and B cells, while maintaining a F +44 (0) 20 7813 8578 normal level and function of NK cells. This form of SCID is caused by autosomal recessive mutations in at least three primary genes necessary for V(D)J recombination, RAG1, RAG2, and DCLRE1C (ARTEMIS). DCLRE1C mutations Samples required cause a T and B cell deficient form of SCID that is clinically indistinguishable from a • 5ml venous blood in plastic EDTA RAG1/RAG2 disorder. Infants present with severe recurrent viral, bacterial or fungal bottles (>1ml from neonates) infections and failure-to-thrive. Defects in DCLRE1C can be distinguished from RAG • Prenatal testing must be arranged defects because the former has the additional feature of increased sensitivity to in advance, through a Clinical ionising radiation in bone marrow and fibroblast cells. Genetics department if possible. The DNA crosslink repair 1C gene (DCLRE1C; MIM 605988) encodes ARTEMIS • Amniotic fluid or CV samples which is an essential factor of V(D)J recombination during lymphocyte development should be sent to Cytogenetics for and in the repair of DNA double-strand breaks (DSB) by the non-homologous end dissecting and culturing, with joining (NHEJ) pathway. -
Microhomology-Mediated End Joining: a Back-Up Survival Mechanism Or Dedicated Pathway? Agnel Sfeir1,* and Lorraine S
TIBS 1174 No. of Pages 14 Review Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway? Agnel Sfeir1,* and Lorraine S. Symington2,* DNA double-strand breaks (DSBs) disrupt the continuity of chromosomes and Trends their repair by error-free mechanisms is essential to preserve genome integrity. MMEJ is a mutagenic DSB repair Microhomology-mediated end joining (MMEJ) is an error-prone repair mecha- mechanism that uses 1–16 nt of fl nism that involves alignment of microhomologous sequences internal to the homology anking the initiating DSB to align the ends for repair. broken ends before joining, and is associated with deletions and insertions that mark the original break site, as well as chromosome translocations. Whether MMEJ is associated with deletions and insertions that mark the original MMEJ has a physiological role or is simply a back-up repair mechanism is a break site, as well as chromosome matter of debate. Here we review recent findings pertaining to the mechanism of translocations. MMEJ and discuss its role in normal and cancer cells. RPA prevents MMEJ by inhibiting annealing between MHs exposed by Introduction end resection. Our cells are constantly exposed to extrinsic and intrinsic insults that cause several types of DNA Recent studies implicate DNA Polu fl lesions, including highly toxic breaks in icted on both strands of the double helix. To counteract (encoded by PolQ) in a subset of MMEJ the harmful effects of these double-strand breaks (DSBs), cells evolved specialized mechanisms events, particularly those associated to sense and repair DNA damage. The repair of DSBs is required to preserve genetic material, but with insertions at the break site. -
DOE Systems Biology Knowledgebase Implementation Plan
DOE Systems Biology Knowledgebase Implementation Plan As part of the U.S. Department of Energy’s (DOE) Office of Science, the Office of Biological and Environmental Research (BER) supports fundamental research and technology development aimed at achieving predictive, systems-level understand- ing of complex biological and environmental systems to advance DOE missions in energy, climate, and environment. DOE Contact Susan Gregurick 301.903.7672, [email protected] Office of Biological and Environmental Research U.S. Department of Energy Office of Science www.science.doe.gov/Program_Offices/BER.htm Acknowledgements The DOE Office of Biological and Environmental Research appreciates the vision and leadership exhibited by Bob Cottingham and Brian Davison (both from Oak Ridge National Laboratory) over the past year to conceptualize and guide the effort to create the DOE Systems Biology Knowledgebase Implementation Plan. Furthermore, we are grateful for the valuable contributions from about 300 members of the scientific community to organize, participate in, and provide the intellectual output of 5 work- shops, which culminated with the implementation plan. The plan was rendered into its current form by the efforts of the Biological and Environmental Research Information System (Oak Ridge National Laboratory). The report is available via • www.genomicscience.energy.gov/compbio/ • www.science.doe.gov/ober/BER_workshops.html • www.systemsbiologyknowledgebase.org Suggested citation for entire report: U.S. DOE. 2010. DOE Systems Biology Knowledgebase Implementation Plan. U.S. Department of Energy Office of Science (www.genomicscience.energy.gov/compbio/). DOE Systems Biology Knowledgebase Implementation Plan September 30, 2010 Office of Biological and Environmental Research The document is available via genomicscience.energy.gov/compbio/. -
Structural Mechanism of DNA-End Synapsis in the Non- Homologous End Joining Pathway for Repairing Double-Strand Breaks: Bridge Over Troubled Ends
This is a repository copy of Structural mechanism of DNA-end synapsis in the non- homologous end joining pathway for repairing double-strand breaks: bridge over troubled ends. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/154931/ Version: Accepted Version Article: Wu, Q orcid.org/0000-0002-6948-7043 (2019) Structural mechanism of DNA-end synapsis in the non-homologous end joining pathway for repairing double-strand breaks: bridge over troubled ends. Biochemical Society Transactions, 47 (6). pp. 1609-1619. ISSN 0300-5127 https://doi.org/10.1042/bst20180518 © 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. This is an author produced version of a paper published in Biochemical Society Transactions. Uploaded in accordance with the publisher's self-archiving policy. Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ -
A Novel Role of the Dna2 Translocase Function in DNA Break Resection
Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press A novel role of the Dna2 translocase function in DNA break resection Adam S. Miller,1,4 James M. Daley,1,4 Nhung Tuyet Pham,2 Hengyao Niu,3 Xiaoyu Xue,1 Grzegorz Ira,2 and Patrick Sung1 1Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA; 2Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA; 3Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, Indiana 47405, USA DNA double-strand break repair by homologous recombination entails nucleolytic resection of the 5′ strand at break ends. Dna2, a flap endonuclease with 5′–3′ helicase activity, is involved in the resection process. The Dna2 helicase activity has been implicated in Okazaki fragment processing during DNA replication but is thought to be dispen- sable for DNA end resection. Unexpectedly, we found a requirement for the helicase function of Dna2 in end re- section in budding yeast cells lacking exonuclease 1. Biochemical analysis reveals that ATP hydrolysis-fueled translocation of Dna2 on ssDNA facilitates 5′ flap cleavage near a single-strand–double strand junction while at- tenuating 3′ flap incision. Accordingly, the ATP hydrolysis-defective dna2-K1080E mutant is less able to generate long products in a reconstituted resection system. Our study thus reveals a previously unrecognized role of the Dna2 translocase activity in DNA break end resection and in the imposition of the 5′ strand specificity of end resection. [Keywords: DNA repair; double-strand break; end resection; homologous recombination] Supplemental material is available for this article.