DNA repair responses to PARP1
PARP1 encompasses a broad scope of DNA repair responses which makes it an attractive candidate for therapeutic inhibition, either alone or in combination with cancer chemotherapy or radiotherapy. Inhibition of PARP1 has potential for use in cancer treatment particularly by increasing tumor sensitivity to chemotherapeutic agents that damage DNA and by inducing synthetic lethality in tumor cells that are highly dependent on PARP1 due to deficiencies in DNA repair proteins (e.g., BRCA1/2).
Other mechanisms by which PARP exerts its effects are through rapid mitochondrial dysfunction with membrane permeability transition, NAD+ depletion, and translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. Inhibition/manipulation of other components of the PARP pathway, including PAR and PARG may therefore, be valuable therapeutic interventions not only for cancer, but for other disease states.
In collaboration with MD Anderson Cancer Center, a highly specific toolkit has been developed and validated to analyse PARP1 in a panel of control and siRNA knockdown cell lysates by multiple immunoassays. This toolkit can specifically and quantitatively distinguish PARP1 from 17 other PARP family members using highly specific antibodies and optimised methods.
Most clinically used PARP inhibitors bind to conserved regions in the PARP domains that permits cross-selectivity with other PARPs containing homologous catalytic domains. Thus, the differences between therapeutic effects and unwanted side effects resulting from pan-PARP inhibition compared to selective inhibition are not well understood. The development and use of more selective agents targeting other domains that make up PARPs, will help answer important questions concerning PARP inhibitors as chemotherapy. A clear understanding of the inhibition profiles of PARP inhibitors will not only enhance the understanding of the biology of individual PARPs, but may provide improved therapeutic options for patients.
Do not hesitate to contact us to test this new toolkit!