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Abstract

Despite undisputed achievements of cancer research and numerous breakthroughs, benefits for patients in terms of prolonged survival time have not been as high as expected. Despite the rapid development of new ways to treat cancers, most patients are still treated with conventional approaches like radiation therapy or chemotherapy. Radio- and chemotherapy induce DNA damage thereby activating the DNA damage response and DNA damage response outcomes like apoptosis to eliminate cancer cells. However, many tumours become resistant to therapy creating a need for new innovative therapeutic strategies. The tumour suppressor p53 is a key effector of the DNA damage response and thus plays a pivotal role in cell fate-decision making upon genotoxic stress. Thus, enhancing p53 activity would be an intriguing approach to increase cancer cell chemosensitivity. In this study, TBL1 was identified as a novel regulator of p53. In unstressed cells, RNA-Sequencing analysis showed that knockdown of TBL1 induced the expression of a subset of p53 target genes. Mechanistically, I found that TBL1 and p53 bind to each other in vitro and in vivo and that both bind to the promotors of the p53 target genes CDKN1A and BBC3 in the absence of p53 activation. Moreover, chromatin immunoprecipitation analysis showed that TBL1 depletion increases the presence of activating histone marks and in parallel, decreases repressive histone marks on the p21 and the PUMA promoter. These findings suggest that (1.) in absence of stress, a subset of p53 promoters are pre-occupied by p53 and (2.) the activity of promoter-bound p53 is suppressed by TBL1 through an epigenetic mechanism. TBL1 is a subunit of the NCoR/SMRT repressor complexes. Knockdown of the co-repressor NCoR and histone deacetylase HDAC3, which is a part of the complex, phenocopies the knockdown of TBL1 and induces p53 target gene expression and increases activating histone acetylation at the p21 and the PUMA promoter indicating that TBL1 represses p53 target gene expression by recruiting co-repressors. Functionally, I found that TBL1 depletion sensitizes colorectal cancer cells to 5-Fluorouracil or Nutlin-3a treatment. Taken together, my work identified TBL1 as a repressor of p53 activity, suggesting a novel strategy to be exploited in the future to chemosensitize cancer cells.