Influence of DNA DSB repair on cell sensitivity to chloroethylating cytostatics

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The main objective of this renewal application is to continue research on the role of DNA double-strand break (DSB) repair and, specifically, the role of homologous recombination in the resistance of tumour (glioblastoma) cells to chloroethylating anticancer drugs (CENU). The repair of DNA inter strand cross links (ICL) induced by CENU in proliferating cells is a complex, multistep process, which is a key node in the tumour cell resistance to this group of chemotherapeutics. The role of proteins involved in DNA damage signaling and ICL repair and the chronological order of their activation will be elucidated. According to our model, in response to CENU critical DSB are formed replication dependently during the repair process at replication forks stalled by ICL. The generated DSB are highly cytotoxic lesions whose repair is accomplished by homologous recombination (HR). Within the frame of the proposed renewal, we wish to continue our research on CENU-induced signaling, DSB repair and cell death pathways. We plan to extend our investigations with methods for down-regulation or inhibition of HR proteins and analyze the effect on the cellular sensitivity in glioblastoma cells, for which CENU are applied in therapy. In addition, we will study the effect of chronic treatment with CENU on the expression of HR proteins in glioblastoma cell lines in vitro and in xenografts in mice. The data will help to clarify the involvement of recombinational repair in the development of cellular resistance to CENU during chemotherapy.