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Lecture 5

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BIOL 205

An Oncogene-Induced DNA Damage Model for Cancer Development Thanos D. Halazonetis, Vassilis G. Gorgoulis, Jiri Bartek Of all types of DNA damage, DNA double-strand breaks (DSBs) pose the greatest challenge to cells. One might have, therefore, anticipated that a sizable number of DNA DSBs would be incompatible with cell proliferation. Yet recent experimental findings suggest that, in both precancerous lesions and cancers, activated oncogenes induce stalling and collapse of DNA replication forks, which in turn leads to formation of DNA DSBs. This continuous formation of DNA DSBs may contribute to the genomic instability that characterizes the vast majority of human cancers. In addition, in precancerous lesions, these DNA DSBs activate p53, which, by inducing apoptosis or senescence, raises a barrier to tumor progression. Breach of this barrier by various mechanisms, most notably by p53 mutations, that impair the DNA damage response pathway allows cancers to develop. Thus, oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations Science 319:1352 (2008) Broken chromosomes can arise by insertion of a single- stranded DNA nick Any agent that blocks ssNick TOPOISOMERASE Topoisomerase can result in a single stranded nick eg camptothecin – A cancer chemotherapy drug Double-stranded break Double-strand break repair is essential Thymine for life! dimer TT Break caused by Torsional stress or Specific enzymes Repetitive sequences that stall Polymerase TT eg (CTGCTGCTG)n Causes breaks in Huntington’s disease Eukaryotes have a highly ordered chromosome structure-new complexities to DNAsynth esis histones, nucleosomes, solenoids E. colition slower than • 24 hours cultured mammalian cells Chapter 2, Fig 2-4 pg35 Metaphase chromosome Packing density lets a metre of DNAfit in a cell nucleus Condensed scaffold Scaffold Solenoid Lodish ~147 bp H2A -dimer H2B H3 tetramer H4 H1 -linker Lodish . Replisome: must copy parental DNA strands, disassemble nucleosome in parental and reassemble in daughter molecules Chromatin assembly factor-1 Old histones- to the daughter molecules Proliferating cell nuclear antigen (Just a name for the complex Beta-clamp) DNA replication proceeds in two directions- similar to E. coli Figure 7-22 A/T rich  1000 growing forks In 23 human chromosomes DNA replication proceeds in two directions Cell cycle protein cdc6 joins at the origin of replication Origins of replication not evenly distributed Gene rich regions (Euchromatin) appears to be replicated first followed by heterochromatin later in S phase The replication problem at chromosome ends Figure 7-25 TELOMERE TELOMERE On lagging strand when last primer Removed –leaves a terminal gap If replicated chromosome would become shorter Telomere lengthening Figure 7-26a Telomeres contain Tandem repeats of Telomerase contains Short DNA sequence RNA (red) that anneals to 3’ DNA overhang TTAGGGTTAGGGTTAGGG 10-15 kb in human Polymerase activity of Chromosome ends Telomerase elongates RNA moves along DNA so that 3’ end Extended further Polymerase activity of Telomerase elongates Telomere lengthening Figure 7-26b Repaired chromosome end The telomeric cap structure Telomeres stabilize chromosomes by preventing loss of genomic information Telomere repeats associate with proteins to protect Chromosome ends from the cell’s DNA repair machinery -might see ends as dble-stranded breaks Werner syndrome causes premature aging Age 15 Age 48 Figure 7-28 Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2205-10. Epub 2007 Feb 6. Telomere dysfunction as a cause of genomic instability in Werner syndrome. Crabbe L, Jauch A, Naeger CM, Holtgreve-Grez H, Karlseder J. Regulatory Biology Department, The Salk Institute for Biological Studies. Abstract Werner syndrome (WS) is a rare human premature aging disease caused by mutations in the gene encoding the RecQ helicase WRN. (Part of Telomerase) In addition to the aging features, this disorder is marked by genomic instability, associated with an elevated incidence of cancer. Several lines of evidence suggest that telomere dysfunction is associated with the aging phenotype of the syndrome; however, the origin of the genomic instability observed in WS cells and the reason for the high incidence of cancer in WS have not been established. We previously proposed that WRN helicase activity was necessary to prevent dramatic telomere loss during DNA replication. Here we demonstrate that replication-associated telomere loss is responsible for the chromosome fusions found in WS fibroblasts. Moreover, using metaphase analysis we show that telomere elongation by telomerase can significantly reduce the appearance of new chromosomal aberrations in cells lacking WRN, similar to complementation of WS cells with WRN. Our results suggest that the genome instability in WS cells depends directly on telomere dysfunction, linking chromosome end maintenance to chromosomal aberrations in this disease. Crabbe L et al. PNAS 2007;104:2205-2210 ©2007 by National Academy of Sciences Jack W. Szostak Carol W. Greider Elizabeth H. Blackburn The Nobel Prize in Physiology or Medicine 2009 for discovery of "how chromosomes are protected by telomeres and the enzyme telomerase • cancer cells have the ability to divide infinitely and yet preserve their telomeres. How do they escape cellular senescence? • cancer cells often have increased telomerase activity. It was therefore proposed that cancer might be tre
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