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
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
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