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  <head>
    <title>091-01 DNA replication, telomeres, genome surveillance, and repair pathways</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="DNA replication, telomeres, and repair">
      <outline text="Copying principles">
        <outline text="Antiparallel strands, five-prime-to-three-prime synthesis">
          <outline text="Extension only from a free three-prime hydroxyl"/>
        </outline>
        <outline text="Semiconservative: old strand templates new"/>
        <outline text="Pairing, active-site geometry, proofreading">
          <outline text="Residual errors corrected after synthesis"/>
        </outline>
        <outline text="Genome maintenance is a network"/>
      </outline>
      <outline text="Origins and the fork">
        <outline text="Thousands of origins across chromosomes"/>
        <outline text="Licensing in late mitosis and gap one">
          <outline text="Inactive helicases loaded"/>
        </outline>
        <outline text="Synthesis-phase kinases fire a subset">
          <outline text="Activation blocks relicensing: copied once"/>
        </outline>
        <outline text="Dormant origins rescue stalled regions"/>
        <outline text="Helicase unwinds, single-strand binders protect"/>
        <outline text="Topoisomerases cut and reseal to relieve strain"/>
        <outline text="Primase makes RNA-DNA primers">
          <outline text="Replicative polymerases cannot start de novo"/>
        </outline>
      </outline>
      <outline text="Strand synthesis and chromatin restoration">
        <outline text="Leading strand continuous toward fork"/>
        <outline text="Lagging strand as Okazaki fragments">
          <outline text="Primers removed, gaps filled, ligase seals"/>
        </outline>
        <outline text="Polymerase epsilon leading, delta lagging"/>
        <outline text="PCNA sliding clamp gives processivity">
          <outline text="Clamp loaders use ATP"/>
        </outline>
        <outline text="Histones recycled and new ones deposited"/>
        <outline text="Epigenetic marks re-established by reader-writers"/>
      </outline>
      <outline text="Fork stress">
        <outline text="Lesions, bound proteins, transcription, low nucleotides"/>
        <outline text="Checkpoint kinases stabilise forks">
          <outline text="Restrain origin firing and delay cycle"/>
        </outline>
        <outline text="Fork reversal protects ends"/>
        <outline text="Recombination restarts collapsed forks"/>
        <outline text="Unresolved stress: breaks and rearrangements">
          <outline text="Major source of cancer evolution"/>
        </outline>
      </outline>
      <outline text="Telomeres">
        <outline text="Repetitive DNA-protein caps"/>
        <outline text="Incomplete end copying and nucleolytic shortening"/>
        <outline text="Shelterin stops ends looking like breaks"/>
        <outline text="Critical dysfunction: checkpoints and fusions">
          <outline text="Breakage-fusion cycles"/>
        </outline>
        <outline text="Telomerase: reverse transcriptase with RNA template">
          <outline text="Germ cells, stem cells, lymphocytes, most cancers"/>
        </outline>
        <outline text="Alternative lengthening by recombination"/>
        <outline text="Shortening limits replication, maintenance immortalises"/>
      </outline>
      <outline text="Lesions and early correction">
        <outline text="Lesion is chemistry, mutation is fixed sequence"/>
        <outline text="Repair restores, tolerates, or introduces errors"/>
        <outline text="Proofreading exonuclease acts immediately"/>
        <outline text="Mismatch repair after replication">
          <outline text="Excises a stretch of the new strand"/>
        </outline>
        <outline text="Lynch syndrome">
          <outline text="Microsatellite instability"/>
          <outline text="Screen tumours, then interpret the cause"/>
        </outline>
      </outline>
      <outline text="Excision and direct repair">
        <outline text="Base excision for small non-distorting lesions">
          <outline text="Glycosylase leaves an abasic site"/>
          <outline text="Endonuclease, processing, fill, ligate"/>
        </outline>
        <outline text="PARP detects single-strand breaks">
          <outline text="Homologous-repair-deficient tumours: synthetic lethality"/>
        </outline>
        <outline text="Nucleotide excision for bulky distortions">
          <outline text="Global-genome versus transcription-coupled"/>
        </outline>
        <outline text="Xeroderma pigmentosum: skin and eye cancer"/>
        <outline text="Cockayne spectrum: growth and neurological disease"/>
        <outline text="Direct reversal: MGMT suicide reaction">
          <outline text="Silencing raises alkylating-agent sensitivity"/>
        </outline>
      </outline>
      <outline text="Double-strand breaks and crosslinks">
        <outline text="Homologous recombination uses sister chromatid">
          <outline text="Favoured in synthesis and gap two"/>
          <outline text="Resection, RAD51 filament, strand invasion"/>
        </outline>
        <outline text="BRCA variants impair homologous repair">
          <outline text="Genomic scars, secondary mutations restore"/>
        </outline>
        <outline text="Classical end joining throughout the cycle">
          <outline text="Essential for antigen-receptor rearrangement"/>
          <outline text="May leave small insertions or deletions"/>
        </outline>
        <outline text="Alternative end joining uses microhomology"/>
        <outline text="Crosslinks need nucleases, bypass, recombination">
          <outline text="Fanconi: marrow failure, anomalies, cancer"/>
        </outline>
      </outline>
      <outline text="Tolerance, signalling, and testing">
        <outline text="Translesion polymerases bypass damage">
          <outline text="Lower fidelity, switch back essential"/>
        </outline>
        <outline text="ATM responds to double-strand breaks">
          <outline text="Ataxia, telangiectasia, radiosensitivity"/>
        </outline>
        <outline text="ATR responds to single-stranded DNA"/>
        <outline text="p53: arrest, senescence, repair, apoptosis"/>
        <outline text="Repair capacity measured indirectly">
          <outline text="Match the test to the biological question"/>
        </outline>
      </outline>
    </outline>
  </body>
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