ESR8: “Targeting telomeres in cancer cells”

EPFL (J. Lingner group): Targeting telomeres in cancer cells

i. Objective of research: Identify the factors that suppress oxidative damage at telomeres and attack telomeres in tumors.

ii. Current state of the art: Telomeres are the nucleoprotein structures at the ends of chromosomes. They are essential for genome stability and they regulate cellular lifespan and tissue renewal. Telomeres are particularly sensitive to reactive oxygen species (ROS) and recent data demonstrate that ROS-damaged telomeres inhibit telomerase activity. Thus, oxidative damage at telomeres can lead to telomere shortening, cellular senescence and apoptosis. This will contribute to organismal aging and may culminate in organ failure. On the other hand, telomere targeting by ROS may also provide an opportunity to inhibit telomerase in cancer cells, which depend on this enzyme for their immortal phenotype. At present, the antioxidant enzyme peroxiredoxin 1 (PRDX1), which reduces hydrogen peroxide to water and the MTH1 phosphatase, which converts oxidized nucleotides to monophosphates are known to counteract oxidative damage at telomeres. In addition, base-excision repair removes oxidative lesions from telomeres. However, the picture of which ROS-protective pathways and DNA repair enzymes contribute to telomere stability is far from complete. Here, we aim at systematically identifying the antioxidant enzymes and DNA repair factors that protect telomeres from ROS. We will determine how the telomeric proteome changes upon oxidative damage and exploit this knowledge to inhibit telomerase in cancer cells.

iii. Research methodology and approach: We will pursue three major approaches. First, we will determine which of the cell’s armory of antioxidant enzymes in addition to PRDX1 and MTH1 contribute to telomere protection. Therefore, we will delete the genes for various peroxidases, peroxiredoxins and DNA glycosylases and determine their epistatic relationships for telomere protection and telomere length maintenance under oxidative stress conditions. Second, we will determine how the telomeric chromatin changes upon exposure to oxidative stress. Therefore, we will apply the quantitative telomeric chromatin isolation protocol (QTIP), which was pioneered in our laboratory and compare intact and ROS-damaged telomeric chromatin by mass spectrometry. This analysis will unravel the telomeric DDR that is triggered upon oxidative stress and identify the DNA repair enzymes that associate with telomeres to remove damaged lesions. Third, we will inactivate antioxidant systems identified in approaches 1 and 2 and test if we can efficiently target telomeres in cancer cells and inhibit telomerase.

iv. Originality and innovative aspects of the ESR project: We will identify the mechanisms that protect telomeres from oxidative damage. This knowledge will unravel the conditions that optimally safeguard telomeres in healthy tissues during aging and uncover opportunities to attack telomeres in cancer cells.

v. Integration of the ESR project to the overall research programme: Our ESR will work with the Jacobs group on the refinement of QTIP protocols, with the Mailand group on chromatin by mass spectrometry methodologies and with Genevia on the development of novel mass spectrometry analysis pipelines.