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Title: Functional characterization of the human protein deleted in breast cancer 1 (DBC1) involvement in the DNA damage response
Author: Magni, Martina
ISNI:       0000 0004 5991 5723
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2016
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The DNA damage response (DDR) is an intricate signalling network established by eukaryotic cells in order to manage the insults to their DNA, arising both from exogenous and from endogenous sources. Thanks to the activation of DDR, cells can block cell cycle progression, to have time to repair the DNA lesions; alternatively, in presence of irreparable damages, cells are committed to apoptosis or senescence, to prevent the replication of damaged genomes, because mutations could be maintained, leading to genomic instability and predisposition to cancer development. One of the proteins recently found to play an important role in the DDR is DBC1 (deleted in breast cancer 1, CCAR2). In particular, DBC1 is a substrate of ATMjATR and a biological inhibitor of the deacetylase SIRT1, the main protein involved in p53 deacetylation. DBC1, through its physical interaction with SIRT1, blocks its deacetylase activity, preserving p53 acetylation and activation and promoting p53-dependent apoptosis. The data presented in this thesis further characterize the mechanism through which DBC1 regulates SIRT1, as I found that it co-operates with Chk2 and the proteasome activator REGy to exert this function. Moreover, these studies unravel a novel role for DBC1 in the repair of heterochromatic DNA lesions through the promotion of Chk2 activity towards KAP1, a Chk2 substrate involved in the modulation of chromatin remodelling. In addition, the data obtained with a genome wide expression analysis of cells lacking DBC1 revealed a crosstalk between DBC1 and TSPYL2, a protein that we found to playa crucial role in the modulation of p53 activation and induction of apoptosis, by regulating the activity of SIRTl and p300. Overall, these studies extend the knowledge of DBCl functions in DDR and DNA repair, and report for the first time a novel role for TSPYL2 in the regulation of p53 activation upon DNA lesions.
Supervisor: Delia, Domenico ; Behrens, Axel Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available