DNA Damage Response: From Tumourigenesis to Therapy

Abstract

The deoxyribonucleic acid (DNA) damage response (DDR) pathway is a surveillance network, whereby lesions are eliminated from DNA to ensure genomic integrity. The DDR detects aberrant DNA and chromosomal structures and elicits a multifaceted response network to coordinate multiple cellular processes, including regulation of the cell cycle, DNA repair, replication and, under certain circumstances, the triggering of programmed cell death. However, when the DDR is dysregulated, genomic integrity is not ensured, which may lead to tumourigenesis. Paradoxically, although genomic instability is a hallmark of many cancers, many conventional cancer treatments elicit the generation of additional DNA damage to exploit inherent DDR faults present in tumour cells. In addition, new‚Äźtargeted DDR inhibitors are currently being developed to enhance therapeutic indexes, including those that are synthetically lethal in particular tumour cell types, providing exciting new therapeutic avenues for cancer treatment. The challenge is how to identify the patients most receptive to these treatments.

Key Concepts:

  • Genome stability is critical to prevent tumourigenesis.

  • Cell cycle checkpoints and DNA repair exist to prevent faulty genetic information from passing onto daughter cells.

  • Many cancer types exhibit defective DNA repair pathways.

  • DNA repair is an ideal therapeutic target for cancer.

  • Cancers exhibit multiple chromosomal alterations.

  • Inherited mutations in DNA repair genes can cause chromosomal instability disorders.

Keywords: DNA damage response; DNA repair; genomic stability; tumourigenesis; synthetic lethality; cell cycle checkpoint; homologous recombination; nonhomologous end joining; cancer

Figure 1.

Schematic representation of the DNA damage response pathway. In this model, DNA damage is recognised by sensors, which transmit the signal to the ATM/ATR protein kinases. ATM‐/ATR‐dependent signals are then transduced to the Chk1 and Chk2 protein kinases by a series of adaptors and signal modifiers. End points for the DNA damage response, including cell cycle arrest, DNA repair, gene transcription and apoptotic cell death, are shown.

Figure 2.

A central role of ATM/ATR in DNA damage checkpoint pathways. Activation mechanisms of ATM/ATR are discussed in the article. Activated proteins signal the presence of DNA damage by phosphorylating targets involved in cell cycle arrest. ATM primarily regulates these phosphorylation events in response to IR (DSBs) and ATR controls it after exposure of cells to UV light and replication arrest (stalled forks). In addition to CHK1/CHK2 phosphorylation discussed in the article, ATM‐dependent phosphorylation of p53 on Ser‐15, which modulates the transactivation potential of p53, and of Mdm2 on Ser‐395, an E3 ligase that targets p53 for degradation, is also shown. Mdm2 phosphorylation inhibits the Mdm2–p53 interaction, leading to stabilisation of p53. Further, p21 is shown as downstream effector of p53, which inhibits the activity of Cdk2/Cyclin E/A.

Figure 3.

DNA repair genes maintain genomic stability. When cells lack functional repair proteins, they fail to repair DSBs correctly, leading to genomic instability and the accumulation of mutations. These events trigger cell cycle checkpoints, resulting in cell cycle arrest or death of affected cells. However, if the checkpoints are inactivated by mutations (e.g. p53), this can lead to tumourigenesis.

Figure 4.

Synthetic lethality occurs when inhibition of a single pathway or gene alone does not cause lethality but does so in combination with inhibition of another pathway or gene (e.g. the synthetically lethal combination of BRCA1 and PARP1 inhibition).

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Bain, Amanda L, Mastrocola, Adam S, Tibbetts, Randal S, and Khanna, Kum Kum(Apr 2014) DNA Damage Response: From Tumourigenesis to Therapy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006107.pub2]