DOCSLIB.ORG

Spontaneous DNA Damage Propels Tumorigenicity Cell Research (2017) 27:720-721

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Spontaneous DNA Damage Propels Tumorigenicity Cell Research (2017) 27:720-721 720 Cell Research (2017) 27:720-721. © 2017 IBCB, SIBS, CAS All rights reserved 1001-0602/17 $ 32.00 RESEARCH HIGHLIGHT www.nature.com/cr Spontaneous DNA damage propels tumorigenicity Cell Research (2017) 27:720-721. doi:10.1038/cr.2017.43; published online 31 March 2017 High levels of endogenously gen- (TP53/p53) and the histone variant H2A as “self-inflicted” or spontaneous DSBs erated DNA damage drive oncogen- histone family member X (H2AFX/ (spDSBs), originated in viable cancer esis, sustain malignant progression H2AX). This multi-pronged cascade cells independently of ROS and RS and increase therapy resistance. In also comprises auto-activation steps, (as they occurred before S phase entry) a paper recently published in Cell feedback loops and a close interplay, through the order of events involving: Research, Liu and colleagues added and possibly redundancy, with the (1) the partial permeabilization of the additional insights into this topic by ATR serine/threonine kinase (ATR) outer mitochondrial membrane, (2) the uncovering a novel intrinsic source network [6]. release of cytochrome c1 (CYC1) from of double-strand breaks that fosters A wide range of evidence dem- mitochondria, (3) sublethal activation the aggressiveness and stemness of onstrates that unrepaired DSBs can of executioner caspases (caspase 3 malignant cells. promote tumorigenesis by inducing (CASP3), CASP6 and CASP7), and DNA double-strand breaks (DSBs) DNA mutation(s) and karytotypic (4) cleavage of chromatin DNA by the are a type of DNA damage characterized aberration(s) [7]. Moreover, established apoptotic nucleases endonuclease G by the severance of both strands of the cancer cells often show increased DSB (ENDOG) and DNA fragmentation DNA duplex. Besides being produced formation accompanied by an extensive factor β (DFFB/CAD) (Figure 1). This by exogenous genotoxins, these cyto- DDR rewiring, encompassing defects circuitry was elegantly unveiled by toxic lesions can arise from multiple in pathway(s) for DNA repair and/or CRISPR/Cas9 gene editing-mediated endogenous sources, including (1) the overactivation of the ATM and ATR knockout and epistatic experiments metabolic by-products, mostly reactive axes [4]. This holds true also for cancer revealing limited nuclease activation oxygen species (ROS); (2) prolonged stem cells (CSCs) [8], which are the in CASP3−/−, CASP3−/−CASP6−/− and stalling in DNA replication fork pro- subset of immature, self-renewing and CASP3−/−CASP6−/−CASP7−/− cancer gression as this occurs during repli- multipotent cells within the tumor mass cells, as well as a significant decrease cation stress (RS); (3) chromosome driving cancer initiation and evolution of spDSBs in tumor cells deficient for missegregation events; (4) telomere [9]. Logically, DDR-related molecules executioner caspases, ENDOG or CAD shortening; and (5) chromothripsis, a are hence regarded as candidate targets [10]. This mechanism is reminiscent to phenomenon associated with the forma- for effective anticancer therapies [4]. that observed upon exogenous perturba- tion of micronuclei [1-3]. Endogenous In a recent paper published by Cell tions [11], even though it occurred in DSBs are boosted by features associated Research, the group of Chuan-Yuan Li unperturbed conditions. with (pre)malignancy, such as increased reports an alternative, intriguing point of In subsequent experiments, Liu et proliferation rate, metabolic rewiring, view about the source of endogenously al. provided evidence in favor of the activated oncogenes, deficiencies in induced DSBs and their contribution to role of spDSBs in sustaining cancer cell DNA damage response (DDR), karyo- cancer evolution [10]. When perform- tumorigenicity and stemness potential. typic aberration(s) or chromosomal ing a comparative analysis of a panel of They demonstrated that the subpopula- instability (CIN) [4, 5]. malignant, immortalized/untransformed tion of cancer cells with elevated levels Irrespective of their origin, DSBs are and primary cell lines previously syn- of spDSBs (spDSBshigh) displayed quickly detected by the ATM serine/ chronized in the G1 phase, these authors higher clonogenicity in soft-agar assay threonine kinase (ATM). Upon binding found high levels of endogenously in- and grew more efficiently when xeno- to DSBs, ATM activates one or more duced DSBs exclusively in tumor cells. grafted in nude mice than the spDSBslow branches of DDR by phosphorylating The presence of DSBs was assessed fraction. In line with this evidence, factors involved in DNA damage repair, by quantifying foci containing γH2AX strategies aimed at minimizing spDSBs cell cycle checkpoint and/or regulated and tumor protein p53 binding protein 1 (e.g., by knocking out effector caspases cell death, such as the checkpoint kinase (TP53BP1/53BP1) and by the COMET or knocking down pro-apoptotic BCL2 2 (CHEK2/CHK2), tumor protein p53 assay. These lesions, which were dubbed proteins) and boosting spDSBs (e.g., SPRINGER NATURE | Cell Research | www.nature.com/cr 721 by irradiating spDSBslow cells with low Figure 1 Mechanism and consequences doses of x-rays) dwindled and enhanced of spDSB formation in tumors. spDSBs in cancer cells are generated via a mechanism the in vitro clonogenicity and in vivo involving the release from mitochondria of tumorigenicity of malignant cells, re- sublethal amounts of ENDOG and CYC1, spectively [10]. which in turn unleashes CAD via the ac- The increase in tumor aggressiveness tivation of CASP3. This is followed by the translocation of ENDOG and CAD from the was associated with the constitutive cytosol to the nucleus, where these nucle- phosphorylation/activation of ATM. ases catalyze DNA cleavage. Upon their Activated ATM ultimately ignited the generation, spDSBs ignite an ATM/NF-κB/ pro-tumorigenic nuclear factor-kappaB STAT3 cascade that promotes malignant tumorigenicity and stemness. (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways instead of triggering DDR. Thus, knockout of executioner caspases, Ilio Vitale1, 2, ENDOG or CAD, reduced the level Guido Kroemer3, 4, 5, 6, 7, 8, 9 of phosphorylated ATM (pATM) and 1Department of Biology, University of Rome “Tor STAT3 (pSTAT3), and abrogated NF-κB Vergata”, Rome 00133, Italy; 2Regina Elena Na- activation. In addition, cells deficient tional Cancer Institute, Rome 00144, Italy; 3Uni- for ATM did not constitutively activate versité Paris Descartes/Paris V, Sorbonne Paris 4 the NF-κB/STAT3 axis, and displayed Cité, Paris 75006, France; Université Pierre et Marie Curie/Paris VI, Paris 75006, France; reduced soft-agar colony-forming abil- 5Equipe 11 labellisée Ligue contre le Cancer, ity and in vivo tumor growth [10]. In Centre de Recherche des Cordeliers, Paris 75006, these experimental settings, knockout France; 6INSERM, U1138, Paris 75006, France; 7 of ATR abolished the clonogenic and Metabolomics and Cell Biology Platforms, −/− Gustave Roussy Comprehensive Cancer Institute, tumorigenic potential of ATM cancer Villejuif 94805, France; 8Pôle de Biologie, Hôpi- cells, confirming the functional inter- tal Européen Georges Pompidou, AP-HP, Paris relationship between these DDR kinases colorectal cancer patients display ongo- 75015, France; 9Karolinska Institute, Department that has previously been reported [6]. ing RS response, at baseline, including of Women’s and Children’s Health, Karolinska University Hospital, Stockholm 17176, Sweden Finally, taking advantage of patient- the overactivation of ATM, associated Correspondence: Ilio Vitalea, Guido Kroemerb derived glioma cells, Liu and colleagues with TP53 mutations and increased aE-mail: [email protected] demonstrated that the subpopulation chromosomal content [12]. It will be bE-mail: [email protected] expressing the CSC marker prominin interesting to analyze (1) whether the 1 (PROM1/CD133) displayed higher TP53 status and/or aberrant karyotype References levels of spDSBs, pATM and pSTAT3 play a role in spDSB generation, (2) what is the mechanism preventing DDR 1 Crasta K, Ganem NJ, Dagher R, et al. Na- than the CD133-negative subpopula- ture 2012; 482:53-58. tion. By employing CRISPR/Cas9 execution upon spDSB-mediated ATM 2 Janssen A, van der Burg M, Szuhai K, et al. technology on these patient-derived activation, and (3) whether a threshold Science 2011; 333:1895-1898. glioma cells, Liu et al. demonstrated level of spDSB tolerability exists and, 3 Zeman MK, Cimprich KA. Nat Cell Biol if so, might be exploited for therapeutic 2014; 16:2-9. that ATM knockout decreased the CSC 4 O’Connor MJ. Mol Cell 2015; 60:547-560. fraction. This was accompanied by the purposes. 5 Vitale I, Manic G, Senovilla L, et al. Trends downregulation of STAT3 and resulted Importantly, the study of Liu and Cancer 2015; 1:124-135. in diminished sphere-growing ability, coauthors support the development of 6 Marechal A, Zou L. Cold Spring Harb Per- biomarker-driven anti-cancer strategies spect Biol 2013; 5:a012716. clonogenicity and in vivo tumor growth 7 Halazonetis TD, Gorgoulis VG, Bartek J. [10]. In these experimental settings, the based on the inhibition of the ATM or Science 2008; 319:1352-1355. forced expression of constitutively ac- ATR axis to deplete aggressive cancer 8 Maugeri-Sacca M, Bartucci M, De Maria R. tive STAT3 rescued the stemness and (stem) cells bearing high levels of Mol Cancer Ther 2012; 11:1627-1636. spDSBs and overactivated ATM/ATR. 9 Kreso A, Dick JE. Cell Stem Cell 2014; tumorigenic potential of patient-derived 14:275-291. glioma cells. To fully translate this evidence into the 10 Liu X, Li F, Huang Q, et al. Cell Res 2017; Reportedly, CSCs of distinct tissue clinics, it appears urgent to identify spe- 27:764-783. origins constitutively activate DDR to cific markers of spDSBs and to elucidate 11 Ichim G, Lopez J, Ahmed SU, et al. Mol the precise origin of spDSBs, and the Cell 2015; 57:860-872. resist genotoxic perturbations [8]. In this 12 Manic G, Signore M, Sistigu A, et al. Gut context, our own observations indicate mechanisms and consequences of their 2017; pii:gutjnl-2016-312623. that a subset of CSCs derived from formation during tumorigenesis. www.cell-research.com | Cell Research | SPRINGER NATURE.
Load more

Recommended publications
  • CPTC-TP53BP1-1 (CAB079980) Immunohistochemistry Immunofluorescence
    CPTC-TP53BP1-1 (CAB079980) Uniprot ID: Q12888 Protein name: TP53B_HUMAN Full name: TP53-binding protein 1 Function: Double-strand break (DSB) repair protein involved in response to DNA damage, telomere dynamics and class-switch recombination (CSR) during antibody genesis (PubMed:12364621, PubMed:22553214, PubMed:23333306, PubMed:17190600, PubMed:21144835, PubMed:28241136). Plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage by promoting non-homologous end joining (NHEJ)- mediated repair of DSBs and specifically counteracting the function of the homologous recombination (HR) repair protein BRCA1 (PubMed:22553214, PubMed:23727112, PubMed:23333306). In response to DSBs, phosphorylation by ATM promotes interaction with RIF1 and dissociation from NUDT16L1/TIRR, leading to recruitment to DSBs sites (PubMed:28241136). Recruited to DSBs sites by recognizing and binding histone H2A monoubiquitinated at 'Lys-15' (H2AK15Ub) and histone H4 dimethylated at 'Lys-20' (H4K20me2), two histone marks that are present at DSBs sites (PubMed:23760478, PubMed:28241136, PubMed:17190600). Required for immunoglobulin class-switch recombination (CSR) during antibody genesis, a process that involves the generation of DNA DSBs (PubMed:23345425). Participates in the repair and the orientation of the broken DNA ends during CSR (By similarity). In contrast, it is not required for classic NHEJ and V(D)J recombination (By similarity). Promotes NHEJ of dysfunctional telomeres via interaction with PAXIP1 (PubMed:23727112). Subcellular
    [Show full text]
  • NBN Gene Analysis and It's Impact on Breast Cancer
    Journal of Medical Systems (2019) 43: 270 https://doi.org/10.1007/s10916-019-1328-z IMAGE & SIGNAL PROCESSING NBN Gene Analysis and it’s Impact on Breast Cancer P. Nithya1 & A. ChandraSekar1 Received: 8 March 2019 /Accepted: 7 May 2019 /Published online: 5 July 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Single Nucleotide Polymorphism (SNP) researches have become essential in finding out the congenital relationship of structural deviations with quantitative traits, heritable diseases and physical responsiveness to different medicines. NBN is a protein coding gene (Breast Cancer); Nibrin is used to fix and rebuild the body from damages caused because of strand breaks (both singular and double) associated with protein nibrin. NBN gene was retrieved from dbSNP/NCBI database and investigated using computational SNP analysis tools. The encrypted region in SNPs (exonal SNPs) were analyzed using software tools, SIFT, Provean, Polyphen, INPS, SNAP and Phd-SNP. The 3’ends of SNPs in un-translated region were also investigated to determine the impact of binding. The association of NBN gene polymorphism leads to several diseases was studied. Four SNPs were predicted to be highly damaged in coding regions which are responsible for the diseases such as, Aplastic Anemia, Nijmegan breakage syndrome, Microsephaly normal intelligence, immune deficiency and hereditary cancer predisposing syndrome (clivar). The present study will be helpful in finding the suitable drugs in future for various diseases especially for breast cancer. Keywords NBN . Single nucleotide polymorphism . Double strand breaks . nsSNP . Associated diseases Introduction NBN has a more complex structure due to its interaction with large proteins formed from the ATM gene which is NBN (Nibrin) is a protein coding gene, it is also known as highly essential in identifying damaged strands of DNA NBS1, Cell cycle regulatory Protein P95, is situated on and facilitating their repair [1].
    [Show full text]
  • RIDDLE Immunodeficiency Syndrome Is Linked to Defects in 53BP1-Mediated DNA Damage Signaling
    RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling Grant S. Stewart*†, Tatjana Stankovic*, Philip J. Byrd*, Thomas Wechsler‡, Edward S. Miller*, Aarn Huissoon§, Mark T. Drayson¶, Stephen C. West‡, Stephen J. Elledge†ʈ, and A. Malcolm R. Taylor* *Cancer Research UK, Institute for Cancer Studies, Birmingham University, Vincent Drive, Edgbaston, Birmingham B15 2TT, United Kingdom; ‡Cancer Research UK, Clare Hall Laboratories, London Research Institute, South Mimms, Hertfordshire EN6 3LD, United Kingdom; §Department of Immunology, Birmingham Heartlands Hospital, Birmingham, B9 5SS, United Kingdom; ¶Division of Immunity and Infection, Birmingham University Medical School, Vincent Drive, Edgbaston, Birmingham B15 2TT, United Kingdom; and ʈHoward Hughes Medical Institute, Department of Genetics, Harvard Partners Center for Genetics and Genomics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115 Contributed by Stephen J. Elledge, September 6, 2007 (sent for review July 6, 2007) Cellular DNA double-strand break-repair pathways have evolved with an alternative constant region (e.g., ␣, ␥, ␧) to generate to protect the integrity of the genome from a continual barrage of different Ig isotypes e.g., IgA, IgG, and IgE (2). potentially detrimental insults. Inherited mutations in genes that During the process of CSR, it has been hypothesized that two control this process result in an inability to properly repair DNA closely positioned single-stranded DNA nicks result in the damage, ultimately
    [Show full text]
  • Product Sheet CG1021
    ATM Antibody Applications: WB, IF Detected MW: 350 kDa Cat. No. CG1021 Species & Reactivity: Human, Mouse Isotype: Rabbit IgG BACKGROUND APPLICATIONS ATM (Ataxia telangiectasia mutated) and ATR Application: *Dilution: (Ataxia telangiectasia and Rad3 related) are WB 1:500-1,000 closely related kinases that are activated by DNA IP n/d damage. These serine-threonine protein kinases IHC n/d are part of the phosphatidylinositol-3 kinase-like ICC n/d kinase (PIKK) family. Upon recruitment by the DNA damage binding proteins/complexes (ATRIP FACS n/d for ATR; MRN for ATM), ATM/ATR initiate the DNA IF 1:100-1:200 damage checkpoint by phosphorylating a number *Optimal dilutions must be determined by end user. of key proteins. Once activated, the checkpoint leads to cell cycle arrest and either DNA repair or apoptosis. ATM is activated by double stranded QUALITY CONTROL DATA breaks and phosphorylates Chk2, whilst ATR is activated by single strand breaks and phosphorylates Chk1.1 ATM activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. It recognizes the substrate consensus sequence [ST]-Q and phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism.2 ATM functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. Both ATM and ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability.3 Mutations in ATM gene are associated with ataxia telangiectasia, an autosomal recessive disorder.
    [Show full text]
  • 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).
    [Show full text]
  • PRODUCT INFORMATION TP53BP1 BRCT Domains (Human Recombinant) Item No
    PRODUCT INFORMATION TP53BP1 BRCT domains (human recombinant) Item No. 14171 • Batch No. XXXX Overview and Properties Synonyms: Tumor Protein p53 binding Protein 1, Tumor Suppressor p53-binding Protein 1 Source: Recombinant human N-terminal GST-tagged protein expressed in E. coli amino acids 1,717-1,972 (N- and C-terminal truncation) Uniprot No.: Q12888 Batch specific information can be found on the Batch Specific Insert or by contacting Technical Support Molecular Weight: 55.1 kDa Storage: -80°C (as supplied) Stability: ≥6 months Purity: batch specific Supplied in: 50 mM Tris-HCl, pH 8.0, containing 150 mM sodium chloride and 20% glycerol Protein Concentration: batch specific mg/ml Image(s) 1 2 3 4 250 kDa · · · · · · · 150 kDa · · · · · · · 100 kDa · · · · · · · 75 kDa · · · · · · · 50 kDa · · · · · · · 37 kDa · · · · · · · 25 kDa · · · · · · · 20 kDa · · · · · · · Lane 1: MW Markers Lane 2: TP53BP1 BRCT domains (1 µg) Lane 3: TP53BP1 BRCT domains (2 µg) Lane 4: TP53BP1 BRCT domains (5 µg) Representative gel image shown; actual purity may vary between each batch. WARNING CAYMAN CHEMICAL THIS PRODUCT IS FOR RESEARCH ONLY - NOT FOR HUMAN OR VETERINARY DIAGNOSTIC OR THERAPEUTIC USE. 1180 EAST ELLSWORTH RD SAFETY DATA ANN ARBOR, MI 48108 · USA This material should be considered hazardous until further information becomes available. Do not ingest, inhale, get in eyes, on skin, or on clothing. Wash thoroughly after handling. Before use, the user must review the complete Safety Data Sheet, which has been sent via email to your institution. PHONE: [800] 364-9897 WARRANTY AND LIMITATION OF REMEDY [734] 971-3335 Buyer agrees to purchase the material subject to Cayman’s Terms and Conditions.
    [Show full text]
  • Ubch7 Regulates 53BP1 Stability and DSB Repair
    UbcH7 regulates 53BP1 stability and DSB repair Xiangzi Hana,1, Lei Zhanga,1, Jinsil Chunga,1, Franklin Mayca Pozoa, Amanda Trana, Darcie D. Seachrista, James W. Jacobbergerb, Ruth A. Keria, Hannah Gilmorec, and Youwei Zhanga,2 aDepartment of Pharmacology, bDivision of General Medical Sciences, Case Comprehensive Cancer Center, School of Medicine, and cUniversity Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH 44106 Edited by Tony Hunter, The Salk Institute for Biological Studies, La Jolla, CA, and approved November 3, 2014 (received for review May 8, 2014) DNA double-strand break (DSB) repair is not only key to genome and generation of one-ended DSBs. Such one-ended DSBs re- stability but is also an important anticancer target. Through an quire HR, but not NHEJ, to repair (8). In contrast, repair of one- shRNA library-based screening, we identified ubiquitin-conjugat- ended DSBs by NHEJ leads to radial chromosomes and cell death ing enzyme H7 (UbcH7, also known as Ube2L3), a ubiquitin E2 (12–14). Therefore, stabilization of 53BP1 by UbcH7 depletion enzyme, as a critical player in DSB repair. UbcH7 regulates both increased the sensitivity of cancers cells to CPT and other DNA the steady-state and replicative stress-induced ubiquitination damaging agents. Our data suggest a novel strategy in enhancing and proteasome-dependent degradation of the tumor suppressor the anticancer effect of radiotherapy or chemotherapy through p53-binding protein 1 (53BP1). Phosphorylation of 53BP1 at the N terminus is involved in the replicative stress-induced 53BP1 degra- stabilizing or increasing 53BP1. dation. Depletion of UbcH7 stabilizes 53BP1, leading to inhibition Results of DSB end resection.
    [Show full text]
  • Tumor Suppressor and DNA Damage Response Panel 2
    Tumor suppressor and DNA damage response panel 2 (55 analytes) Gene Symbol Target protein name UniProt ID (& link) Modification* *blanks mean the assay detects the ACT Actin; ACTA2 ACTA1 ACTB ACTG1 ACTC1 ACTG2 Q562L2 non‐modified peptide sequence CASC5 cancer susceptibility candidate 5 Q8NG31 pS767 CASC5 cancer susceptibility candidate 5 Q8NG31 CASP3 caspase 3, apoptosis‐related cysteine peptidase P42574 pS26 CDC25B cell division cycle 25 homolog B (S. pombe) P30305 pS16 CDC25B cell division cycle 25 homolog B (S. pombe) P30305 pS323 CDC25B cell division cycle 25 homolog B (S. pombe) P30305 CDC25C cell division cycle 25 homolog B (S. pombe) P30307 pS216 CDC25C cell division cycle 25 homolog B (S. pombe) P30307 CDCA8 cell division cycle associated 8 Q53HL2 pT16 CDK1 cyclin‐dependent kinase 1 P06493 pT161 CDK1 cyclin‐dependent kinase 1 P06493 CDK7 cyclin‐dependent kinase 7 P50613 pT17 CHEK1 CHK1 checkpoint homolog (S. pombe) O14757 pS286 CHEK2 CHK2 checkpoint homolog (S. pombe) O96017 pS379 CHEK2 CHK2 checkpoint homolog (S. pombe) O96017 pT387 CHEK2 CHK2 checkpoint homolog (S. pombe) O96017 GAPDH Glyceraldehyde‐3‐phosphate dehydrogenase P04406 LAT linker for activation of T cells O43561 pS224 LMNB1 lamin B1 P20700 pT2; pS23 LMNB1 lamin B1 P20700 pT2 LMNB1 lamin B1 P20700 pS23 MCM6 minichromosome maintenance complex component 6 Q14566 pS762 MCM6 minichromosome maintenance complex component 6 Q14566 MDM2 Mdm2, transformed 3T3 cell double minute 2, p53 binding protein (mouse) Q00987 pS166 MDM2 Mdm2, transformed 3T3 cell double minute 2, p53 binding protein (mouse) Q00987 MKI67 antigen identified by monoclonal antibody Ki‐67 P46013 pT181 MKI67 antigen identified by monoclonal antibody Ki‐67 P46013 MKI67 antigen identified by monoclonal antibody Ki‐67 P46013 pT246 MRE11A MRE11 meiotic recombination 11 homolog A (S.
    [Show full text]
  • Targeted Mass Spectrometry Enables Quantification of Novel
    cancers Article Targeted Mass Spectrometry Enables Quantification of Novel Pharmacodynamic Biomarkers of ATM Kinase Inhibition Jeffrey R. Whiteaker 1 , Tao Wang 1, Lei Zhao 1, Regine M. Schoenherr 1, Jacob J. Kennedy 1, Ulianna Voytovich 1, Richard G. Ivey 1, Dongqing Huang 1, Chenwei Lin 1, Simona Colantonio 2, Tessa W. Caceres 2, Rhonda R. Roberts 2, Joseph G. Knotts 2, Jan A. Kaczmarczyk 2, Josip Blonder 2, Joshua J. Reading 2, Christopher W. Richardson 2, Stephen M. Hewitt 3, Sandra S. Garcia-Buntley 2, William Bocik 2, Tara Hiltke 4, Henry Rodriguez 4, Elizabeth A. Harrington 5, J. Carl Barrett 5, Benedetta Lombardi 5, Paola Marco-Casanova 5, Andrew J. Pierce 5 and Amanda G. Paulovich 1,* 1 Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA 98109, USA; [email protected] (J.R.W.); [email protected] (T.W.); [email protected] (L.Z.); [email protected] (R.M.S.); [email protected] (J.J.K.); [email protected] (U.V.); [email protected] (R.G.I.); [email protected] (D.H.); [email protected] (C.L.) 2 Cancer Research Technology Program, Antibody Characterization Lab, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA; [email protected] (S.C.); [email protected] (T.W.C.); [email protected] (R.R.R.); [email protected] (J.G.K.); [email protected] (J.A.K.); [email protected] (J.B.); [email protected] (J.J.R.); [email protected] (C.W.R.); [email protected] (S.S.G.-B.); [email protected] (W.B.) 3 Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Citation: Whiteaker, J.R.; Wang, T.; Institute, National Institute of Health, Bethesda, MD 20892, USA; [email protected] Zhao, L.; Schoenherr, R.M.; Kennedy, 4 Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA; J.J.; Voytovich, U.; Ivey, R.G.; Huang, [email protected] (T.H.); [email protected] (H.R.) D.; Lin, C.; Colantonio, S.; et al.
    [Show full text]
  • Differential Expression Profile Analysis of DNA Damage Repair Genes in CD133+/CD133‑ Colorectal Cancer Cells
    ONCOLOGY LETTERS 14: 2359-2368, 2017 Differential expression profile analysis of DNA damage repair genes in CD133+/CD133‑ colorectal cancer cells YUHONG LU1*, XIN ZHOU2*, QINGLIANG ZENG2, DAISHUN LIU3 and CHANGWU YUE3 1College of Basic Medicine, Zunyi Medical University, Zunyi; 2Deparment of Gastroenterological Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi;3 Zunyi Key Laboratory of Genetic Diagnosis and Targeted Drug Therapy, The First People's Hospital of Zunyi, Zunyi, Guizhou 563003, P.R. China Received July 20, 2015; Accepted January 6, 2017 DOI: 10.3892/ol.2017.6415 Abstract. The present study examined differential expression cells. By contrast, 6 genes were downregulated and none levels of DNA damage repair genes in COLO 205 colorectal were upregulated in the CD133+ cells compared with the cancer cells, with the aim of identifying novel biomarkers for COLO 205 cells. These findings suggest that CD133+ cells the molecular diagnosis and treatment of colorectal cancer. may possess the same DNA repair capacity as COLO 205 COLO 205-derived cell spheres were cultured in serum-free cells. Heterogeneity in the expression profile of DNA damage medium supplemented with cell factors, and CD133+/CD133- repair genes was observed in COLO 205 cells, and COLO cells were subsequently sorted using an indirect CD133 205-derived CD133- cells and CD133+ cells may therefore microbead kit. In vitro differentiation and tumorigenicity assays provide a reference for molecular diagnosis, therapeutic target in BABA/c nude mice were performed to determine whether selection and determination of the treatment and prognosis for the CD133+ cells also possessed stem cell characteristics, in colorectal cancer.
    [Show full text]
  • The Thyroid Hormone Receptor Induces DNA Damage and Premature
    Published January 6, 2014 JCB: Article The thyroid hormone receptor induces DNA damage and premature senescence Alberto Zambrano,1 Verónica García-Carpizo,1 María Esther Gallardo,1,3 Raquel Villamuera,1 Maria Ana Gómez-Ferrería,1 Angel Pascual,1 Nicolas Buisine,2 Laurent M. Sachs,2 Rafael Garesse,1,3,4 and Ana Aranda1 1Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain 2Département Régulation, Développement et Diversité Moléculaire, Unité Mixte de Recherche 7221, Centre National de la Recherche Scientifique, Muséum National d’Histoire Naturelle, 75231 Paris, France 3Centro de Investigación Biomédica en Red, 28029 Madrid, Spain 4Instituto de Investigación Sanitaria Hospital 12 de Octubre, 28041 Madrid, Spain here is increasing evidence that the thyroid hormone factor 1) and THRB to the promoters of genes with a key (TH) receptors (THRs) can play a role in aging, can- role on mitochondrial respiration. Increased respiration T cer and degenerative diseases. In this paper, we leads to production of mitochondrial reactive oxygen spe- Downloaded from demonstrate that binding of TH T3 (triiodothyronine) to cies, which in turn causes oxidative stress and DNA dou- THRB induces senescence and deoxyribonucleic acid ble-strand breaks and triggers a DNA damage response (DNA) damage in cultured cells and in tissues of young that ultimately leads to premature senescence of suscepti- hyperthyroid mice. T3 induces a rapid activation of ATM ble cells. Our findings provide a mechanism for integrat- (ataxia telangiectasia mutated)/PRKAA (adenosine mo- ing metabolic effects of THs with the tumor suppressor jcb.rupress.org nophosphate–activated protein kinase) signal transduc- activity of THRB, the effect of thyroidal status on longevity, tion and recruitment of the NRF1 (nuclear respiratory and the occurrence of tissue damage in hyperthyroidism.
    [Show full text]
  • 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.
    [Show full text]