Cellular responses to DNA damage: from molecular insights to new medicines

Speaker: Steve Jackson
Department: Gurdon institute, University of Cambridge
Subject: Cellular responses to DNA damage
Location: Erasmus MC Rotterdam
Date: 27 September 2016
Author: Carolien Bastiaanssen

Jackson began his talk with an introduction to DNA damage and how this damage is repaired. Every day about 2,000,000,000,000,000,000 lesions occur in each person. These lesions are for example caused by replication errors or by exposure to radiation. Different causes lead to different types of lesions including single-strand breaks (SSBs), double-strand breaks (DSBs), insertions, deletions and mismatches. There are many DNA repair pathways to deal with this myriad of lesions, each dedicated to the repair of a certain type of DNA damage. Before the DNA can be repaired, the damage has to be detected, repair factors have to be induced, transcription has to be regulated and the cell cycle might be arrested. This process is referred to as DNA-damage response (DDR). Most of the times the DNA is repaired rapidly and accurately. However, defects in the cellular responses to DNA damage may lead to cancer, premature aging or immune-deficiency.

Extensive knowledge of DNA repair can be used to exploit DNA repair pathways for therapeutic applications. The advantage of these pathways is that there are many druggable targets to inhibit the various DNA repair pathways. This can be used to enhance the efficacy of radiotherapy and chemotherapy. In addition it could reduce the side-effects because lower doses can be used. It is however important that only the cancer cells are targeted, this could be achieved by exploiting the differences between cancer cells and healthy cells. These differences include that cancer cells generally replicate more frequently, they also exhibit enhanced DNA damage loads and they lack DDR pathways. The latter one is often seen as the Achilles’ heel of many cancers.

In 1997 Jackson founded a company called KuDOS Pharmaceuticals (now part of Astrazeneca) which was dedicated to developing cancer therapies based on manipulating the DDR. The most promising compound which has been developed is a poly ADP-ribose polymerase (PARP) inhibitor called olaparib/LynparzaTM. PARP promotes SSB repair and base-excision repair. When it is inhibited, repair is slowed down and PARP is trapped on the DNA. For healthy cells a short period of PARP inhibition is not destructive but cancer cells are very sensitive. For example cancer cells with BRCA1 or BRCA2 mutations cannot repair DSBs efficiently and if PARP is inhibited in those cells, they are confronted with too much DNA damage which they cannot repair. This will eventually lead to cell death.

 

parp-inhibitor
PARP inhibition. PARP is required for the repair SSBs. In case these breaks are not repaired, they lead to the formation of DSBs. In healthy cells this type of lesion is repaired through HR. However in cancer cells that lack efficient HR, PARP inhibition leads to cell death. Source: Piccart, M. et al. An update on PARP inhibitors – moving to the adjuvant setting. Nature Reviews Clinical Oncology 12, 27-41 (2015)

It was interesting to see how fundamental knowledge about the DNA repair mechanisms of cells can be exploited to improve cancer therapy. Research which might have in the first place been driven by the curiosity of scientists, now proves to be of great value in the clinic. It is thereby important to study the differences between cancer cells and healthy cells in order to be able to primarily target the cancer cells and leave the healthy cells intact.

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