Partner: T. Sewastianik

Recent publications
1.Korwek Z., Sewastianik T., Bielak-Żmijewska A., Mosieniak G., Alster O., Moreno-Villaneuva M., Burkle A., Sikora E., Inhibition of ATM blocks the etoposide-induced DNA damage response and apoptosis of resting human T cells, DNA REPAIR, ISSN: 1568-7864, DOI: 10.1016/j.dnarep.2012.08.006, Vol.11, pp.864-873, 2012

It is believed that normal cells with an unaffected DNA damage response (DDR) and DNA damage repair machinery, could be less prone to DNA damaging treatment than cancer cells. However, the anticancer drug, etoposide, which is a topoisomerase II inhibitor, can generate DNA double strand breaks affecting not only replication but also transcription and therefore can induce DNA damage in non-replicating cells. Indeed, we showed that etoposide could influence transcription and was able to activate DDR in resting human T cells by inducing phosphorylation of ATM and its substrates, H2AX and p53. This led to activation of PUMA, caspases and to apoptotic cell death. Lymphoblastoid leukemic Jurkat cells, as cycling cells, were more sensitive to etoposide considering the level of DNA damage, DDR and apoptosis. Next, we used ATM inhibitor, KU 55933, which has been shown previously to be a radio/chemo-sensitizing agent. Pretreatment of resting T cells with KU 55933 blocked phosphorylation of ATM, H2AX and p53, which, in turn, prevented PUMA expression, caspase activation and apoptosis. On the other hand, KU 55933 incremented apoptosis of Jurkat cells. However, etoposide-induced DNA damage in resting T cells was not influenced by KU 55933 as revealed by the FADU assay. Altogether our results show that KU 55933 blocks DDR and apoptosis induced by etoposide in normal resting T cells, but increased cytotoxic effect on proliferating leukemic Jurkat cells. We discuss the possible beneficial and adverse effects of drugs affecting the DDR in cancer cells that are currently in preclinical anticancer trials.


FADU, γH2AX, DSBs, Caspases, KU 55933

Korwek Z.-other affiliation
Sewastianik T.-other affiliation
Bielak-Żmijewska A.-Nencki Institute of Experimental Biology, Polish Academy of Sciences (PL)
Mosieniak G.-Nencki Institute of Experimental Biology, Polish Academy of Sciences (PL)
Alster O.-Nencki Institute of Experimental Biology, Polish Academy of Sciences (PL)
Moreno-Villaneuva M.-University of Konstanz (DE)
Burkle A.-University of Konstanz (DE)
Sikora E.-Nencki Institute of Experimental Biology, Polish Academy of Sciences (PL)