DNA-Schadensantwort und ihre pharmakologische Beeinflussung

DNA damage response and its pharmacological inhibition

Zusammenfassung

Alle chemischen Karzinogene, ionisierende Strahlung und die „klassischen“ gentoxischen Zytostatika greifen die DNA an; darauf beruht ihre gentoxische und toxische Wirkung. Die Aufklärung der Vorgänge, die sich an der geschädigten DNA abspielen, ist folglich essenziell zum Verständnis der Wirkung von Karzinogenen (und damit der Krebsentstehung) wie auch der Wirkung von Zytostatika. Potenziell letale Ereignisse für die Zelle sind DNA-Doppelstrangbrüche (DSB) und Schäden, die die DNA-Replikation blockieren. Die Zelle hat Mechanismen entwickelt, auf diese schwerwiegenden Schäden am Erbgut zu reagieren. Sensorsysteme erkennen die Schäden und leiten das Signal über Kinasen weiter an „Exekutoren“, die bewirken, dass die Zelle entweder in der Zellzyklusprogression inhibiert und DNA-Reparatur verstärkt wird oder durch Apoptoseinduktion zu Grunde geht. Zentrale „player“ in der DNA-Schadenserkennung sind ATM, ATR und DNA-PK, die eine Vielzahl von Proteinen phosphorylieren und dadurch die DNA-Schadensantwort einleiten, in der p53 und BRCA1/2 eine wichtige Rolle spielen. Die pharmakologische Beeinflussung der DNA-Schadensantwort zielt darauf ab, insbesondere DNA-Reparaturvorgänge zu hemmen, um dadurch Tumorzellen, die genetische Defekte haben, selektiv abzutöten (synthetische Letalität) oder sie zu sensibilisieren, um die Wirkung von Krebs-Chemotherapeutika zu verstärken.

Abstract

Chemical carcinogens, ionizing radiation and genotoxic anti-cancer drugs target DNA and DNA damage triggers genotoxicity and cell death. The elucidation of DNA damage-triggered signaling pathways is crucial for understanding the action of carcinogens and cancer initiation and progression as well as the action of genotoxic anti-cancer drugs. Potentially lethal DNA lesions for cells are DNA double-strand breaks and damage which blocks DNA replication. Cells are equipped with sensor systems which recognize the lesions and transduce the signals via kinases to downstream players, which inhibit cell cycle progression and stimulate DNA repair or, alternatively, activate apoptotic pathways. Key players of the DNA damage response (DDR) are the MRN complex and ATM, ATR and DNA-PK, which recognize DNA breaks and phosphorylate a large number of substrates, including CHK proteins, p53 and BRCA1/2. Pharmacological inhibition of DDR aimed at inhibiting the activation of DNA repair functions selectively kills cancer cells that exhibit genetic defects such as BRCA mutations (synthetic letality) and thas ameliorates the effects of anti-cancer drugs on human cells.

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Correspondence to Prof. Dr. B. Kaina.

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Kaina, B., Christmann, M. DNA-Schadensantwort und ihre pharmakologische Beeinflussung. Onkologe 17, 503–512 (2011). https://doi.org/10.1007/s00761-011-2028-6

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Schlüsselwörter

  • DNA-Schadensantwort
  • Signaling
  • Apoptose
  • Zytostatika
  • DNA-Reparatur

Keywords

  • DNA damage response
  • Signaling
  • Apoptosis
  • Anticancer drugs
  • DNA repair