Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Previous Page Next Page

Cells have evolved a number of pathways that comprise a network of proteins that sense, signal and/or repair DNA, which are collectively referred to as the DNA Damage Response (DDR; see figure 4) [1-5]. There are several hundred proteins implicated in the DDR. Key proteins that signal DNA damage to cell cycle checkpoints and DNA repair pathways include ATM (ataxia-telangiectasia mutated), ATR (ATM- and Rad3-related), and DNA-PKcs (DNA-dependent protein kinase, catalytic subunit) kinases [2, 6-9].

Once DNA damage is detected, repair mechanisms can include [1]:

  • Base excision repair (BER) for single strand breaks.
  • Nucleotide excision repair (NER) for repair of bulky adducts.
  • Mismatch repair (MMR) for mis-paired bases.
  • Homologous recombination repair (HRR) for double strand break repair.
  • Non-homologous end joining (NHEJ) for double strand break repair.
  • Micro-homology mediated end joining (MMEJ) for double strand break repair.

Cells with excessive or unrepairable DNA may enter cell cycle arrest and/or trigger apoptosis, a p53-dependent mechanism [3].

Figure 4: DNA damage repair (DDR) signalling pathways and repair mechanisms

Figure 4: DNA damage repair (DDR) signalling pathways and repair mechanisms

Factors shown are the subset of DDR proteins that are being targeted pharmacologically, including PARP1/2.
Adapted from Gourley, et al., J Clin Oncol 2019

References

  1. O'Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell 2015; 60: 547-560.
  2. Pearl LH, Schierz AC, Ward SE et al. Therapeutic opportunities within the DNA damage response. Nat Rev Cancer 2015; 15: 166-180.
  3. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature 2009; 461: 1071-1078.
  4. Friedberg EC. A brief history of the DNA repair field. Cell Res 2008; 18: 3-7.
  5. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 2004; 73: 39-85.
  6. Corcoran NM, Clarkson MJ, Stuchbery R, Hovens CM. Molecular Pathways: Targeting DNA Repair Pathway Defects Enriched in Metastasis. Clin Cancer Res 2016; 22: 3132-3137.
  7. Marechal A, Zou L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol 2013; 5.
  8. Blackford AN, Jackson SP. ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. Mol Cell 2017; 66: 801-817.
  9. Harper JW, Elledge SJ. The DNA damage response: ten years after. Mol Cell 2007; 28: 739-745.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings