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DNA break caused by Radiation

DNA break caused by Radiation

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01 dn abreak 01 dn abreak Presentation Transcript

  • DNA Strand Breaks and Chromosomal AberrationsWhat is the practical application? 2006/08/19 Sam
  • Recurrent rectal cancerTx 63Gy/35 fractionsPain relief 9 monthsRetreatment less effective?Different patient response?Inducible radioresistance? 2006/08/19 Sam
  • Direct and indirect action of radiationPouget JP, Mather SJ. General aspects of the cellular response to low- and high-LET radiation. Eur J Nucl Med. 2001 Apr;28(4):541-61. 2006/08/19 Sam
  • Representation of single-strand DNA molecule and sites of hydrolyticand oxidative attack. Pouget JP, Mather SJ. General aspects of the cellular response to low- and high-LET radiation. Eur J Nucl Med. 2001 Apr;28(4):541-61. 2006/08/19 Sam
  • Different levels of chromatin organization are shown with a charged particle (arrow) entering from the left creating DNA damage (black dots) along its path.Desai N, Davis E, ONeill P, Durante M, Cucinotta FA, Wu H. Immunofluorescence detection of clustered gamma-H2AX foci induced by HZE-particle radiation. Radiat Res. 2005 Oct;164(4 Pt 2):518-22.Rydberg B. Radiation-induced DNA damage and chromatin structure. Acta Oncol. 2001;40(6):682-5. 2006/08/19 Sam
  • Structure of the nucleosome.(a) One DNA strand is shown in green and the other in brown. H2A is yellow; H2B, red; H3, blue; H4, green.(b) Space-filling model shown from the side. DNA is shown in white; histones are colored as in (a). Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. Molecular Cell Biology. 4th ed. New York: W. H. Freeman & Co.; c2000. 2006/08/19 Sam
  • • 8 histone proteins, 2 from each of 4histone protein families, H4, H3, H2B,and H2A• 3 H2A subfamiles - H2A1-H2A2,H2AZ, and H2AX• in mammals the H2AZ representsabout 10% of the H2A complement, theH2AX represents 2–25% (15%) 2006/08/19 Sam
  • The Cell - A Molecular Approach. 2nd ed. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc; c2000. 2006/08/19 Sam
  • The 30 nm chromatin fiber as the target for DNA damage. Multiple damaged sites Multiple damaged sites (MDS) are created that typically span less than 20 bp of DNA -> DSB. Rydberg B. Radiation-induced DNA damage and chromatin structure. Acta Oncol. 2001;40(6):682-5. 2006/08/19 Sam
  • Schematic representations of the track structure of high and low-LET radiation.Desai N, Davis E, ONeill P, Durante M, Cucinotta FA, Wu H. Immunofluorescence detection of clustered gamma-H2AX foci induced by HZE-particleradiation. Radiat Res. 2005 Oct;164(4 Pt 2):518-22.Fry DE, Schecter WP, Hartshorne MF. The surgeon and acts of civilian terrorism: radiation exposure and injury. J Am Coll Surg. 2006 Jan;202(1):146-54.Pouget JP, Mather SJ. General aspects of the cellular response to low- and high-LET radiation. Eur J Nucl Med. 2001 Apr;28(4):541-61. 2006/08/19 Sam
  • Examples ofRadiation-induced Aberrations 2006/08/19 Sam
  • (a) A situation with 2 DSBs on 2 chromosomes. End-joining reactions can occur among the 4 DSB free ends u, u, v and v.(b) A cell containing a translocation usually clonogenically viable, however which can result in transformation.(c) A dicentric is usually clonogenically lethal. Sachs RK, Hlatky LR, Trask BJ. Radiation-produced chromosome aberrations: colourful clues. Trends Genet. 2000 Apr;16(4):143-6. 2006/08/19 Sam
  • (d) 2 DSBs, but now on 1 chromosome (f) 3 DSBs, on 3 chromosomes;instead of 2. and (g) shows 1 possible outcome(e) 1 possible outcome is a ring. (out of 15). Sachs RK, Hlatky LR, Trask BJ. Radiation-produced chromosome aberrations: colourful clues. Trends Genet. 2000 Apr;16(4):143-6. 2006/08/19 Sam
  • (h) 3 DSBs, but now on only 2 chromosomes. 2 of the 15 possible outcomes are shown in (j) and (k).Sachs RK, Hlatky LR, Trask BJ. Radiation-produced chromosome aberrations: colourful clues. Trends Genet. 2000 Apr;16(4):143-6. 2006/08/19 Sam
  • Lymphocyte metaphase showing typical chromatid damage induced by X-irradiation in G2. b, break; g, gap; sg, small gap.Baria K, Warren C, Eden OB, Roberts SA, West CM, Scott D. Chromosomal radiosensitivity in young cancer patients: possibleevidence of genetic predisposition. Int J Radiat Biol. 2002 May;78(5):341-6. 2006/08/19 Sam
  • Chromosome and chromatid aberrations produced by ionising radiation.Pouget JP, Mather SJ. General aspects of the cellular response to low- and high-LET radiation. Eur J Nucl Med. 2001 Apr;28(4):541-61. 2006/08/19 Sam
  • A normal human fibroblast cell at metaphase, after exposure to a 4 Gy dose of during the preceding interphase. A multiplex - FISH technique was used to ‘paint’ each of the homologous chromosome pairs a unique color. Arrow (a) shows where a segment of chromosome 7 is inserted into chromosome 12; (b) shows a ring derived from chromosome 1. A third pattern, involving 3 chromosomes and 3 breaks, includes (d), (e) and 1 other component. An additional pattern, involving 4 chromosomes and 7 breaks, includes (a)–(c) and some other components.Sachs RK, Hlatky LR, Trask BJ. Radiation-produced chromosome aberrations: colourful clues. Trends Genet. 2000 Apr;16(4):143-6. 2006/08/19 Sam
  • Chromosome analyses were carried out in peripheral lymphocytes of a 13-year-old boy exposed to protracted low dose-rate whole- body and short-time partial-body irradiation from a radiation accident in Estonia in 1994. Up to November 1998, the frequencies of translocations and dicentrics were periodically measured using FISH chromosome painting of the target chromosomes 1, 4 and 12, with a simultaneous pancentromeric probe.Bauchinger M, Schmid E, Braselmann H. Time-course of translocation and dicentric frequencies in a radiation accident case. Int J Radiat Biol.2001 May;77(5):553-7. 2006/08/19 Sam
  • RESULTS: For the yields of dicentrics, an expected rapid temporal decline was found with a half-time of 14.2+/-1.9 months. The yields of reciprocal translocations also revealed a gradual but significant reduction with a half-time of 51.7+/-12.7 months.Bauchinger M, Schmid E, Braselmann H. Time-course of translocation and dicentric frequencies in a radiation accident case. Int J Radiat Biol.2001 May;77(5):553-7. 2006/08/19 Sam
  • The 5 main DNA-repair pathways are:• nucleotide excision repair (NER) (which involvesglobal genome repair (GGR) and transcription-coupledrepair (TCR)),•base excision repair (BER),•mismatch repair (MMR),•homologous recombination (HR)•non-homologous end joining (NHEJ) repair.NER, BER and MMR lead to the excision of thedamaged or mispaired bases,HR and NHEJ allow the repair of DSBs. Huang TT, DAndrea AD. Regulation of DNA repair by ubiquitylation. Nat Rev Mol Cell Biol. 2006 May;7(5):323-34. 2006/08/19 Sam
  • Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001 May 17;411(6835):366-74. 2006/08/19 Sam
  • ODriscoll M, Jeggo PA. The role of double-strand break repair - insights from human genetics. Nat Rev Genet. 2006 Jan;7(1):45-54. 2006/08/19 Sam
  • The Cell - A Molecular Approach. 2nd ed. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc; c2000. 2006/08/19 Sam
  • H2AX is activatedwhen DNA moleculesinside the cell arebroken - such asradiation. 2006/08/19 Sam
  • Downs JA, Jackson SP. Cancer: protective packaging for DNA. Nature. 2003 Aug 14;424(6950):732-4. 2006/08/19 Sam
  • Takahashi A, Ohnishi T. Does gammaH2AX foci formation depend on the presence of DNA double strand breaks? Cancer Lett. 2005 Nov18;229(2):171-9. 2006/08/19 Sam
  • ODriscoll M, Jeggo PA. The role of double-strand break repair - insights from human genetics. Nat Rev Genet. 2006 Jan;7(1):45-54. 2006/08/19 Sam
  • ODriscoll M, Jeggo PA. The role of double-strand break repair - insights from human genetics. Nat Rev Genet. 2006 Jan;7(1):45-54. 2006/08/19 Sam
  • Lobrich M, Kiefer J. Assessing the likelihood of severe side effects in radiotherapy. Int J Cancer. 2006 Jun 1;118(11):2652-6. 2006/08/19 Sam
  • These days peopleseek knowledge, notwisdom. Knowledge is of the past, wisdom is of the future.VERNON COOPER 2006/08/19 Sam
  • “Predictive assays” :laboratory tests designedto predict the response oftumors and/or normal tissuesto radiotherapy on the basis oftheir radiobiologicalcharacteristics. 2006/08/19 Sam
  • Predictive assays2.Reliable3.Reproducible4.Practical 2006/08/19 Sam
  • There is significantvariability in outcomewith respect to bothtumor control probabilityand normal tissuedamage. 2006/08/19 Sam
  • 在基因表現方面,不同的實驗室有時會產生不同的結果。 RNA 的實驗往往需要大件的檢體纔能得到高品質的RNA ,而 RNA 的實驗也比 DNA 實驗昂貴與費時。相對的 DNA 比較穩定也比較容易做出來。使用 singlenucleotide polymorphism (SNP) 來做可以利用較容易取得的檢體如血液、口腔黏膜等組織。 2006/08/19 Sam
  • ATM, TGFB1, XRCC1, XRCC3, SOD2, hHR21, 5557 G->A variant in ATM, Thr/Thr genotype in XRCC3 codon 241Ho AY, Atencio DP, Peters S, Stock RG, Formenti SC, Cesaretti JA, Green S, Haffty B, Drumea K, Leitzin L, Kuten A, Azria D, Ozsahin M,Overgaard J, Andreassen CN, Trop CS, Park J, Rosenstein BS. Genetic predictors of adverse radiotherapy effects: the Gene-PARE project. IntJ Radiat Oncol Biol Phys. 2006 Jul 1;65(3):646-55. 2006/08/19 Sam
  • Chinnaiyan P, Allen GW, Harari PM. Radiation and new molecular agents, part II: targeting HDAC, HSP90, IGF-1R, PI3K, andRas. Semin Radiat Oncol. 2006 Jan;16(1):59-64. 2006/08/19 Sam
  • Choudhury A, Cuddihy A, Bristow RG. Radiation and new molecular agents part I: targeting ATM-ATR checkpoints, DNA repair, and theproteasome. Semin Radiat Oncol. 2006 Jan;16(1):51-8. 2006/08/19 Sam
  • Choudhury A, Cuddihy A, Bristow RG. Radiation and new molecular agents part I: targeting ATM-ATR checkpoints, DNA repair, and theproteasome. Semin Radiat Oncol. 2006 Jan;16(1):51-8. 2006/08/19 Sam
  • Choudhury A, Cuddihy A, Bristow RG. Radiation and new molecular agents part I: targeting ATM-ATR checkpoints, DNA repair, and theproteasome. Semin Radiat Oncol. 2006 Jan;16(1):51-8. 2006/08/19 Sam