<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Inducing and suppressing the alternative\r\nlengthening of telomeres mechanism in\r\ncancer cells"^^ . "Cancer cells extend critically short telomeres either by reactivating the reverse transcriptase telomerase or by employing alternative lengthening of telomeres (ALT). The ALT mechanism depends on proteins involved in DNA repair and homologous recombination (HR). High-throughput sequencing is\r\nincreasingly used to analyze whole genome sequences (WGS) and gene expression in patient samples, and potentially, provides a rich resource of information on ALT. However, in ALT cancers the only recurrent mutations identified so far are in the chromatin remodeler ATRX (alpha thalassemia/ mental retardation syndrome X-linked), the histone chaperone DAXX (death domain associated protein), and the histone variant H3.3. In addition, gene expression signatures for patient stratification into ALTpositive and ALT-negative as well as a systematic approach to identify genes involved in telomere maintenance (TM) and in particular ALT via functional annotation are currently missing. One wellestablished hallmark of ALT is the dislocation of the PML (promyelocytic leukemia) protein to telomeres in ALT-associated PML nuclear bodies (APBs). These colocalizations are reliable biomarkers for ALT-positive tumors, but the functional role of PML during the development of ALT remains elusive. In this thesis, I have addressed the issues raised above by work in three areas: First, the TelNet database was developed as a comprehensive compilation of TM genes. Proteins involved in TM were collected, functionally categorized, and evaluated by applying a significance score. In addition to various search modes, a statistics page was implemented for TM pathway analysis and for prediction of the active TM mechanism (TMM). Second, ALT candidate genes were identified by gene expression analysis using four different approaches and isogenic cellular systems: (i) ALT suppression by HDAC inhibitor SAHA in U2OS cells, (ii) ALT induction by ASF1 depletion in HeLa cells with long telomeres (LT), (iii) reduced ALT induction capacity of the ASF1 depletion in HeLa LT cells by SAHA treatment, and (iv) deletion of EST2 (ever shorter telomeres 2), the telomerase protein subunit, in budding yeast to generate survivors that maintain telomeres by type II recombination, equivalent to the human ALT mechanism. A differential gene expression analysis comparing perturbed cells with the unperturbed control cells revealed a positive correlation of WNT and TGFb signaling with the presence of ALT and on the other hand a negative association of TNF/ NFkB/ MAP kinase signaling. Furthermore, a role as potential ALT enhancers was predicted for KCTD15 and TNNC1. In budding\r\nyeast type II survivors, approximately 30 genes showed a relatively small albeit statistically significant change in gene expression as compared to pre-senescent cells. Genes within the iron-regulon were overrepresented among downregulated genes, including FIT1, FIT2, ARN2, and FRE4, indicating stress response. Third, I investigated the functional role of PML in the ALT pathway by recruiting PML to telomeres in cells with and without ALT background. The formation of artificial APBs induced telomere clustering and subsequently increased the abundance of extrachromosomal repeats as an ALT feature in both ALT-positive and ALT-negative cells. The results obtained in this thesis facilitate patient stratification based on deep sequencing data according to their TM mechanism and provide a better understanding of the functional role of APBs for ALT."^^ . "2018" . . . . . . . "Delia"^^ . "Braun"^^ . "Delia Braun"^^ . . . . . . "Inducing and suppressing the alternative\r\nlengthening of telomeres mechanism in\r\ncancer cells (PDF)"^^ . . . "1 Braun 2018 PhD Thesis_print_FINAL_gedruckt.pdf"^^ . . . "Inducing and suppressing the alternative\r\nlengthening of telomeres mechanism in\r\ncancer cells (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #25661 \n\nInducing and suppressing the alternative \nlengthening of telomeres mechanism in \ncancer cells\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .