Tankyrase 1 and 2: a key role in DNA repair
TNKS1 is recruited to DNA repair foci (green spots) that colocalize with the DNA damage response marker γ-H2AX (red spots). The recruitment depends on MDC1, as in MDC1 depleted cells TNKS1 does not form DNA repair foci (green diffused signal).
PLoS Genet Feb. 4, 2016
Feb. 4, 2016
Different damaging agents like exposure to UV or environmental chemicals continuously challenge the integrity of our genome. When the DNA breaks, a cascade of proteins is assembled at each lesion to signal its presence and to ensure proper DNA repair. Since the discovery of DNA repair pathways that was awarded by the Nobel Prize for Chemistry last year, a plethora of signaling and DNA repair proteins have been identified and characterized. One of these proteins is called MDC1 (The mediator of the checkpoint 1). MDC1 amplifies the signals emitted by the DNA lesions and leads to cell cycle arrest until the breaks are repaired. This protein is also essential for repairing the DNA lesions. Despite the fact that the role of MDC1 in DNA repair is well known, how it exert its function is not understood.
A study by the team of Evi SOUTOGLOU, published in the Plos Genetics on February 4th, 2016 focused on the mechanism of action of MDC1 seeking interacting partners of this protein. They found that MDC1 interacts with two proteins called Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2), members of the Poly ADP ribose polymerase group (PARP). The study shows that Tankyrase 1 and 2 (TNKSs) are recruited to broken DNA via MDC1 and participate in the repair of DNA breaks.
Mutations or reduction in TNKS1 and 2 protein levels in cells impede cell cycle arrest after DNA damage, a process important for maintaining genomic stability. Moreover, TNKSs control Homology directed repair, a process in which a DNA lesion is repaired in an error free manner by copying an identical DNA sequence from a sister chromosome.
PARP inhibitors have been already successfully used in cancer therapy. The discovery that Tankyrase 1 and 2 play an important role in DNA repair allows to consider new strategies that can be put in place against cancer using the new inhibitors specific for TNKSs released recently.