Association of P53 and MSH2 with Recombinative Repair Complexes During S Phase
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Predictive Value of RAD51 on the Survival and Drug Responsiveness of Ovarian Cancer Yuchen Feng1, Daoqi Wang2, Luyang Xiong3, Guohua Zhen1 and Jiahong Tan4*
Feng et al. Cancer Cell Int (2021) 21:249 https://doi.org/10.1186/s12935-021-01953-5 Cancer Cell International PRIMARY RESEARCH Open Access Predictive value of RAD51 on the survival and drug responsiveness of ovarian cancer Yuchen Feng1, Daoqi Wang2, Luyang Xiong3, Guohua Zhen1 and Jiahong Tan4* Abstract Background: Ovarian cancer has greatly endangered and deteriorated female health conditions worldwide. Refne- ment of predictive biomarkers could enable patient stratifcation and help optimize disease management. Methods: RAD51 expression profle, target-disease associations, and ftness scores of RAD51 were analyzed in ovar- ian cancer using bioinformatic analysis. To further identify its role, gene enrichment analysis was performed, and a regulatory network was constructed. Survival analysis and drug sensitivity assay were performed to evaluate the efect of RAD51 expression on ovarian cancer prognosis. The predictive value of RAD51 was then confrmed in a validation cohort immunohistochemically. Results: Ovarian cancer expressed more RAD51 than normal ovary. RAD51 conferred ovarian cancer dependency and was associated with ovarian cancer. RAD51 had extensive target-disease associations with various diseases, including ovarian cancer. Genes that correlate with and interact with RAD51 were involved in DNA damage repair and drug responsiveness. High RAD51 expression indicated unfavorable survival outcomes and resistance to platinum, taxane, and PARP inhibitors in ovarian cancer. In the validation cohort (126 patients), high RAD51 expression indicated platinum resistance, and platinum-resistant patients expressed more RAD51. Patients with high RAD51 expression had shorter OS (HR 2.968, P < 0.0001) and poorer PFS (HR 2.838, P < 0.0001). RAD51 expression level was negatively cor- related with patients’= survival length. -
The Bloom Syndrome Protein Limits the Lethality Associated with RAD51 Deficiency
Published OnlineFirst March 9, 2010; DOI: 10.1158/1541-7786.MCR-09-0534 Molecular DNA Damage and Cellular Stress Responses Cancer Research The Bloom Syndrome Protein Limits the Lethality Associated with RAD51 Deficiency Kenza Lahkim Bennani-Belhaj1,2, Sébastien Rouzeau1,2, Géraldine Buhagiar-Labarchède1,2, Pauline Chabosseau1,2, Rosine Onclercq-Delic1,2, Emilie Bayart1, Fabrice Cordelières3,4, Jérôme Couturier5,6, and Mounira Amor-Guéret1,2 Abstract Little is known about the functional interaction between the Bloom's syndrome protein (BLM) and the re- combinase RAD51 within cells. Using RNA interference technology, we provide the first demonstration that RAD51 acts upstream from BLM to prevent anaphase bridge formation. RAD51 downregulation was associated with an increase in the frequency of BLM-positive anaphase bridges, but not of BLM-associated ultrafine bridges. Time-lapse live microscopy analysis of anaphase bridge cells revealed that BLM promoted cell survival in the absence of Rad51. Our results directly implicate BLM in limiting the lethality associated with RAD51 deficiency through the processing of anaphase bridges resulting from the RAD51 defect. These findings provide insight into the molecular basis of some cancers possibly associated with variants of the RAD51 gene family. Mol Cancer Res; 8(3); 385–94. ©2010 AACR. Introduction cently, SUMOylation of BLM has been shown to regulate its association with RAD51 and its function in HR-medi- Bloom's syndrome displays one of the strongest known ated repair of damaged replication forks (13). In several correlations between chromosomal instability and a high models, it has been proposed that BLM restarts replication risk of cancer at an early age. -
Mutations in the RAD54 Recombination Gene in Primary Cancers
Oncogene (1999) 18, 3427 ± 3430 ã 1999 Stockton Press All rights reserved 0950 ± 9232/99 $12.00 http://www.stockton-press.co.uk/onc SHORT REPORT Mutations in the RAD54 recombination gene in primary cancers Masahiro Matsuda1,4, Kiyoshi Miyagawa*,1,2, Mamoru Takahashi2,4, Toshikatsu Fukuda1,4, Tsuyoshi Kataoka4, Toshimasa Asahara4, Hiroki Inui5, Masahiro Watatani5, Masayuki Yasutomi5, Nanao Kamada3, Kiyohiko Dohi4 and Kenji Kamiya2 1Department of Molecular Pathology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Hiroshima 734, Japan; 2Department of Developmental Biology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Hiroshima 734, Japan; 3Department of Cancer Cytogenetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Hiroshima 734, Japan; 42nd Department of Surgery, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734, Japan; 51st Department of Surgery, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589, Japan Association of a recombinational repair protein RAD51 therefore, probable that members of the RAD52 with tumor suppressors BRCA1 and BRCA2 suggests epistasis group are altered in cancer. that defects in homologous recombination are responsible To investigate whether RAD54, a member of the for tumor formation. Also recent ®ndings that a protein RAD52 epistasis group, is mutated in human cancer, associated with the MRE11/RAD50 repair complex is we performed SSCP analysis and direct sequencing of mutated in Nijmegen breakage syndrome characterized PCR products using mRNAs from 132 unselected by increased cancer incidence and ionizing radiation primary tumors including 95 breast cancers, 13 sensitivity strongly support this idea. -
Arsenic Disruption of DNA Damage Responses—Potential Role in Carcinogenesis and Chemotherapy
Biomolecules 2015, 5, 2184-2193; doi:10.3390/biom5042184 OPEN ACCESS biomolecules ISSN 2218-273X www.mdpi.com/journal/biomolecules/ Review Arsenic Disruption of DNA Damage Responses—Potential Role in Carcinogenesis and Chemotherapy Clarisse S. Muenyi 1, Mats Ljungman 2 and J. Christopher States 3,* 1 Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA; E-Mail: [email protected] 2 Departments of Radiation Oncology and Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109-2800, USA; E-Mail: [email protected] 3 Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-502-852-5347; Fax: +1-502-852-3123. Academic Editors: Wolf-Dietrich Heyer, Thomas Helleday and Fumio Hanaoka Received: 14 August 2015 / Accepted: 9 September 2015 / Published: 24 September 2015 Abstract: Arsenic is a Class I human carcinogen and is widespread in the environment. Chronic arsenic exposure causes cancer in skin, lung and bladder, as well as in other organs. Paradoxically, arsenic also is a potent chemotherapeutic against acute promyelocytic leukemia and can potentiate the cytotoxic effects of DNA damaging chemotherapeutics, such as cisplatin, in vitro. Arsenic has long been implicated in DNA repair inhibition, cell cycle disruption, and ubiquitination dysregulation, all negatively impacting the DNA damage response and potentially contributing to both the carcinogenic and chemotherapeutic potential of arsenic. Recent studies have provided mechanistic insights into how arsenic interferes with these processes including disruption of zinc fingers and suppression of gene expression. -
Scaffolding Protein SPIDR/KIAA0146 Connects the Bloom Syndrome Helicase with Homologous Recombination Repair
Scaffolding protein SPIDR/KIAA0146 connects the Bloom syndrome helicase with homologous recombination repair Li Wan1, Jinhua Han1, Ting Liu1, Shunli Dong, Feng Xie, Hongxia Chen, and Jun Huang2 Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China Edited by James E. Cleaver, University of California, San Francisco, CA, and approved February 26, 2013 (received for review December 1, 2012) The Bloom syndrome gene product, BLM, is a member of the highly of the SDSA pathway (6, 7). The ability of BLM to yield non- conserved RecQ family. An emerging concept is the BLM helicase crossover products is thought to play a critical role in the avoidance collaborates with the homologous recombination (HR) machinery to of chromosomal rearrangements during the homolog-directed re- help avoid undesirable HR events and to achieve a high degree of pair of chromosomal lesions. As a result, cells defective for BLM fidelity during the HR reaction. However, exactly how such coordina- exhibit elevated rates of sister chromatid exchange (SCE) (19–21). tion occurs in vivo is poorly understood. Here, we identified a protein Upon the occurrence of DNA damage, BLM is able to form termed SPIDR (scaffolding protein involved in DNA repair) as the link discrete foci, where it colocalizes with other DNA repair proteins between BLM and the HR machinery. SPIDR independently interacts (22, 23). However, mechanistically how BLM is recruited to sites with BLM and RAD51 and promotes the formation of a BLM/RAD51- of DNA damage and how it collaborates with other proteins to containing complex of biological importance. Consistent with its role mediate recombination repair remain largely unexplored. -
Epigenetic Regulation of DNA Repair Genes and Implications for Tumor Therapy ⁎ ⁎ Markus Christmann , Bernd Kaina
Mutation Research-Reviews in Mutation Research xxx (xxxx) xxx–xxx Contents lists available at ScienceDirect Mutation Research-Reviews in Mutation Research journal homepage: www.elsevier.com/locate/mutrev Review Epigenetic regulation of DNA repair genes and implications for tumor therapy ⁎ ⁎ Markus Christmann , Bernd Kaina Department of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany ARTICLE INFO ABSTRACT Keywords: DNA repair represents the first barrier against genotoxic stress causing metabolic changes, inflammation and DNA repair cancer. Besides its role in preventing cancer, DNA repair needs also to be considered during cancer treatment Genotoxic stress with radiation and DNA damaging drugs as it impacts therapy outcome. The DNA repair capacity is mainly Epigenetic silencing governed by the expression level of repair genes. Alterations in the expression of repair genes can occur due to tumor formation mutations in their coding or promoter region, changes in the expression of transcription factors activating or Cancer therapy repressing these genes, and/or epigenetic factors changing histone modifications and CpG promoter methylation MGMT Promoter methylation or demethylation levels. In this review we provide an overview on the epigenetic regulation of DNA repair genes. GADD45 We summarize the mechanisms underlying CpG methylation and demethylation, with de novo methyl- TET transferases and DNA repair involved in gain and loss of CpG methylation, respectively. We discuss the role of p53 components of the DNA damage response, p53, PARP-1 and GADD45a on the regulation of the DNA (cytosine-5)- methyltransferase DNMT1, the key enzyme responsible for gene silencing. We stress the relevance of epigenetic silencing of DNA repair genes for tumor formation and tumor therapy. -
Expression of MSH2 and MSH6 on a Tissue Microarray in Patients with Osteosarcoma
ANTICANCER RESEARCH 34: 6961-6972 (2014) Expression of MSH2 and MSH6 on a Tissue Microarray in Patients with Osteosarcoma THORSTEN JENTZSCH1,2, BERNHARD ROBL1, MAREN HUSMANN1, BEATA BODE-LESNIEWSKA3 and BRUNO FUCHS1 1Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zürich, Switzerland; 2Division of Trauma Surgery, Department of Surgery, University Hospital Zürich, Zürich, Switzerland; 3Institute of Surgical Pathology, University Hospital Zürich, Zürich, Switzerland Abstract. Background/Aim: Reliable prognostic factors for and head (4, 5). Following neoadjuvant chemotherapy, surgical the outcome of patients with osteosarcoma (OS) remain elusive. tumor resections provide tissue specimens for the assessment We analyzed the relationship between immunohistochemical of tumor necrosis rate, histology, grading and evaluation of expression of deoxyribonucleic acid (DNA) mismatch repair tumor biomarkers before further adjuvant chemotherapy may (MMR) proteins, MutS protein homolog 2 (MSH2) and MSH6 be initiated (6-8). Despite advances in therapeutic approaches, using a tissue microarray (TMA) with respect to OS patient five-year overall survival rates have been reported as 78% (9) demographics and survival time. Materials and Methods: We and are usually lower for non-responders to chemotherapy retrieved tumor tissue specimens from bone tissue originating (10) and patients with metastasis (11, 12). from surgical primary tumor specimens of OS patients to Albeit the limited number of studies (8, 13-17) on tumor generate a TMA and stained sections with antibodies against biomarkers, these are important for treatment decisions, MSH2 and MSH6. Results: Tumor resections of 67 patients patient discrimination regarding the response to with a mean follow-up of 98 months were evaluated. MSH2 chemotherapy and the incidence of metastasis, prediction of was expressed in nine (13%), MSH6 in ten (15%) and patient survival times and patient education (18-21). -
The Consequences of Rad51 Overexpression for Normal and Tumor Cells
dna repair 7 (2008) 686–693 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/dnarepair Mini review The consequences of Rad51 overexpression for normal and tumor cells Hannah L. Klein ∗ Department of Biochemistry, New York University School of Medicine, NYU Medical Center, 550 First Avenue, New York, NY 10016, United States article info abstract Article history: The Rad51 recombinase is an essential factor for homologous recombination and the Received 11 December 2007 repair of DNA double strand breaks, binding transiently to both single stranded and double Accepted 12 December 2007 stranded DNA during the recombination reaction. The use of a homologous recombination Published on line 1 February 2008 mechanism to repair DNA damage is controlled at several levels, including the binding of Rad51 to single stranded DNA to form the Rad51 nucleofilament, which is controlled through Keywords: the action of DNA helicases that can counteract nucleofilament formation. Overexpression Rad51 protein of Rad51 in different organisms and cell types has a wide assortment of consequences, rang- Overexpression of Rad51 ing from increased homologous recombination and increased resistance to DNA damaging Genomic instability agents to disruption of the cell cycle and apoptotic cell death. Rad51 expression is increased Tumor cell drug resistance in p53-negative cells, and since p53 is often mutated in tumor cells, there is a tendency for Homologous recombination Rad51 to be overexpressed in tumor cells, leading to increased resistance to DNA damage Gene targeting and drugs used in chemotherapies. As cells with increased Rad51 levels are more resis- tant to DNA damage, there is a selection for tumor cells to have higher Rad51 levels. -
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, -
Involvement of Nucleotide Excision and Mismatch Repair Mechanisms in Double Strand Break Repair
250 Current Genomics, 2009, 10, 250-258 Involvement of Nucleotide Excision and Mismatch Repair Mechanisms in Double Strand Break Repair Ye Zhang1,2,*, Larry H. Rohde2 and Honglu Wu1 1NASA Johnson Space Center, Houston, Texas 77058 and 2University of Houston at Clear Lake, Houston, Texas 77058, USA Abstract: Living organisms are constantly threatened by environmental DNA-damaging agents, including UV and ioniz- ing radiation (IR). Repair of various forms of DNA damage caused by IR is normally thought to follow lesion-specific re- pair pathways with distinct enzymatic machinery. DNA double strand break is one of the most serious kinds of damage induced by IR, which is repaired through double strand break (DSB) repair mechanisms, including homologous recombi- nation (HR) and non-homologous end joining (NHEJ). However, recent studies have presented increasing evidence that various DNA repair pathways are not separated, but well interlinked. It has been suggested that non-DSB repair mecha- nisms, such as Nucleotide Excision Repair (NER), Mismatch Repair (MMR) and cell cycle regulation, are highly involved in DSB repairs. These findings revealed previously unrecognized roles of various non-DSB repair genes and indicated that a successful DSB repair requires both DSB repair mechanisms and non-DSB repair systems. One of our recent studies found that suppressed expression of non-DSB repair genes, such as XPA, RPA and MLH1, influenced the yield of IR- induced micronuclei formation and/or chromosome aberrations, suggesting that these genes are highly involved in DSB repair and DSB-related cell cycle arrest, which reveals new roles for these gene products in the DNA repair network. -
The Properties of Msh2–Msh6 ATP Binding Mutants Suggest a Signal
ARTICLE cro Author’s Choice The properties of Msh2–Msh6 ATP binding mutants suggest a signal amplification mechanism in DNA mismatch repair Received for publication, August 19, 2018, and in revised form, September 17, 2018 Published, Papers in Press, September 20, 2018, DOI 10.1074/jbc.RA118.005439 William J. Graham, V‡, Christopher D. Putnam‡§, and X Richard D. Kolodner‡¶ʈ**1 From the ‡Ludwig Institute for Cancer Research San Diego, Departments of §Medicine and ¶Cellular and Molecular Medicine, ʈMoores-UCSD Cancer Center, and **Institute of Genomic Medicine, University of California School of Medicine, San Diego, La Jolla, California 92093-0669 Edited by Patrick Sung DNA mismatch repair (MMR) corrects mispaired DNA bases synthesis (1–6). MMR also acts on some forms of chemically and small insertion/deletion loops generated by DNA replica- damaged DNA bases as well as on mispairs present in hetero- tion errors. After binding a mispair, the eukaryotic mispair rec- duplex DNA intermediates formed during recombination ognition complex Msh2–Msh6 binds ATP in both of its nucle- (1–6). MMR proteins also act in a pathway that suppresses otide-binding sites, which induces a conformational change recombination between homologous but divergent DNAs resulting in the formation of an Msh2–Msh6 sliding clamp that (1–6) and function in a DNA damage response pathway for releases from the mispair and slides freely along the DNA. How- different types of DNA-damaging agents, including some che- ever, the roles that Msh2–Msh6 sliding clamps play in MMR motherapeutic agents (2). As a result of the role that MMR plays remain poorly understood. -
Defective DNA Repair and Chromatin Organization in Patients with Quiescent Systemic Lupus Erythematosus Vassilis L
Souliotis et al. Arthritis Research & Therapy (2016) 18:182 DOI 10.1186/s13075-016-1081-3 RESEARCH ARTICLE Open Access Defective DNA repair and chromatin organization in patients with quiescent systemic lupus erythematosus Vassilis L. Souliotis1,2*, Konstantinos Vougas3, Vassilis G. Gorgoulis3,4 and Petros P. Sfikakis2 Abstract Background: Excessive autoantibody production characterizing systemic lupus erythematosus (SLE) occurs irrespective of the disease’s clinical status and is linked to increased lymphocyte apoptosis. Herein, we tested the hypothesis that defective DNA damage repair contributes to increased apoptosis in SLE. Methods: We evaluated nucleotide excision repair at the N-ras locus, DNA double-strand breaks repair and apoptosis rates in peripheral blood mononuclear cells from anti-dsDNA autoantibody-positive patients (six with quiescent disease and six with proliferative nephritis) and matched healthy controls following ex vivo treatment with melphalan. Chromatin organization and expression levels of DNA repair- and apoptosis-associated genes were also studied in quiescent SLE. Results: Defective nucleotide excision repair and DNA double-strand breaks repair were found in SLE, with lupus nephritis patients showing higher DNA damage levels than those with quiescent disease. Melphalan-induced apoptosis rates were higher in SLE than control cells and correlated inversely with DNA repair efficiency. Chromatin at the N-ras locus was more condensed in SLE than controls, while treatment with the histone deacetylase inhibitor vorinostat resulted in hyperacetylation of histone H4, chromatin decondensation, amelioration of DNA repair efficiency and decreased apoptosis. Accordingly, genes involved in DNA damage repair and signaling pathways, such as DDB1, ERCC2, XPA, XPC, MRE11A, RAD50, PARP1, MLH1, MLH3, and ATM were significantly underexpressed in SLE versus controls, whereas PPP1R15A, BARD1 and BBC3 genes implicated in apoptosis were significantly overexpressed.