PARP and DDR Pathways: Targeting the DNA Damage Response for Cancer Treatment

Our cells, and the DNA they contain, are under constant attack from external factors such as ionizing radiation, ultraviolet light and environmental toxins. Internal cellular processes can also generate metabolites, such as reactive oxygen species, that damage DNA. In most cases, DNA damage results in permanent changes to DNA molecules, including DNA mismatches, single-strand breaks (SSBs), double-strand breaks (DSBs), crosslinking, or chemical alteration of bases or sugars. If left unchecked, DNA damage can cause genome instability, mutations and aberrant transcription, and oncogenic transformation.

PARP DDR pathway for drug discovery

Fortunately, our cells have also evolved multiple pathways to repair damaged DNA, collectively known as the DNA damage response (DDR). The type of repair mechanism depends on the nature of the damage, and whether the damage occurs in mitochondrial or nuclear DNA. These mechanisms have been reviewed extensively (1,2). Recently, considerable attention has focused on pathways for repairing SSBs and DSBs, mediated by the ADP-ribosylating enzyme known as poly (ADP-ribose) polymerase 1, or PARP-1.

What Is PARP-1?

PARP-1 is part of a family of PARP proteins, most of which are found in the nucleus. Although the functions of these proteins vary, they are characterized by common motifs that include a DNA-binding domain, a conserved catalytic domain and a caspase-cleaved domain (3–6). When PARP-1 binds to a SSB or DSB in damaged DNA, it changes conformation and synthesizes a poly (ADP-ribose) or PAR chain while consuming NAD+. These PAR chains, when attached to PARP-1 substrates (including PARP-1 itself), trigger the action of other enzymes that control a host of cellular responses, including DNA repair (7).

The role of PARP-1 in various forms of cell death has been studied extensively. Although multiple, complex pathways are involved, the mechanism typically includes the action of so-called “suicidal proteases” that cleave PARP-1 into specific, smaller fragments that each mediate unique cell death pathways (4). The best-known example is cleavage of PARP-1 by caspase-3 or caspase-7, inhibiting the DNA repair process and ultimately resulting in programmed cell death or apoptosis (4).

Synthetic Lethality

Given the importance of PARP-1 in repairing damaged DNA, it might seem paradoxical that significant drug discovery efforts have been devoted to developing PARP-1 inhibitors. However, in the case of cancer treatments, radiation or chemotherapy are designed to destroy tumor cells by damaging their DNA to the point where cell death is inevitable. In this scenario, it is desirable to prevent the cell’s natural DNA repair mechanisms from functioning. Further, in those cancers caused by defects in one or more DDR pathways, tumor cells divide more rapidly and contain only a subset of functional DDR-associated enzymes compared to normal cells. This difference makes tumor cells easier to target with specific DDR inhibitors that destroy them while sparing normal cells, in a process known as “synthetic lethality” (8,9).

The first PARP inhibitors approved for clinical use employed the synthetic lethality strategy to treat breast and ovarian cancers caused by BRCA mutations (10). Most of the current PARP-1 inhibitors work by binding to the catalytic domain of PARP-1, inhibiting the addition of PAR chains to substrates, and trapping PARP-1 at the site of DNA damage (9). The trapped PARP-1 prevents DNA replication and leads to genomic instability. Further downstream, the release of cytosolic DNA by these replication-deficient cells activates an adaptive immune response, resulting in destruction of the tumor cell (9).

Although our understanding of how PARP inhibitors work has grown considerably over the past decade, there is still much to learn. Challenges, such as resistance to PARP inhibitors and mixed results from combination therapies with PARP inhibitors and chemotherapy (9), must be addressed in clinical settings to improve outcomes. Further research should enable refinement of therapeutic strategies and maximize the potential of this promising class of anticancer agents.

Discover products and technologies to study PARP/DDR pathways with our drug discovery applications page.

References

  1. Chatterjee, N. and Walker, G.C. (2017) Mechanisms of DNA damage, repair and mutagenesis. Environ. Mol. Mutagen. 58(5), 235–263.
  2. Li, L-Y. et al. (2021) DNA repair pathways in cancer therapy and resistance. Front. Pharmacol. 11, 629266.
  3. Boulares, A.H. et al. (1999) Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. J. Biol. Chem. 274(33), 22932–22940.
  4. Chaitanya, G.V. et al. (2010) PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Commun. Signal. 8, 31.
  5. Morales, J.C. et al. (2014) Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit. Rev. Eukaryot. Gene Expr. 24(1), 15–28.
  6. Bai, P. (2015) Biology of poly(ADP-ribose) polymerases: The factotums of cell maintenance. Mol. Cell 58, 947–958.
  7. Ko, H.L. and Ren, E.C. (2012) Functional aspects of PARP1 in DNA repair and transcription. Biomolecules 2, 524–548.
  8. Cheng, B. et al. (2022) Recent advances in DDR (DNA damage response) inhibitors for cancer therapy. Eur. J. Med. Chem. 230, 114109.
  9. Wicks, A.J. et al. (2022) Opinion: PARP inhibitors in cancer—what do we still need to know? Open Biol. 12, 220118.
  10. Faraoni, I. and Graziani, G. (2018) Role of BRCA mutations in cancer treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. Cancers 10, 487.

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Ken Doyle
Ken is a science writer at Promega Corporation. Although his PhD is in molecular biology, he enjoys researching and writing about everything from M-theory to graptolites. When he's not spending time with family or serving his canine and feline overlords, Ken engages in a quest for a mythical creature known as "spare time". If he succeeds, he hopes to return to writing fiction so he can keep his brain in balance.

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