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dc.contributor.advisor Dobbelstein, Matthias Prof. Dr.
dc.contributor.author Klusmann, Ina
dc.date.accessioned 2018-11-21T09:56:00Z
dc.date.available 2018-11-21T09:56:00Z
dc.date.issued 2018-11-21
dc.identifier.uri http://hdl.handle.net/11858/00-1735-0000-002E-E50B-5
dc.language.iso deu de
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 570 de
dc.title The tumour suppressor p53 as a supporter of DNA replication de
dc.type doctoralThesis de
dc.contributor.referee Shcherbata, Halyna PD Dr.
dc.date.examination 2018-08-30
dc.description.abstracteng The tumour suppressor protein p53 is well known for its role in maintaining genetic stability by preventing the propagation of damage onto successive generations of cells. Depending on the extent of damage experienced by a cell, p53 promotes cell cycle arrest to allow for DNA repair or induces apoptosis in cases of severe damage. The canonical functions of p53, commonly referred to as the “guardian of the genome”, imply action only after the damage has occurred within a cell. Our work challenges this view by providing evidence pointing to a more direct and pro-active role for p53 in protecting a cellular genome from damage. p53 activation enhances the processivity of DNA replication and reduces replicative stress, whereas the removal of p53 reduces fork progression. This was observed in tumour-derived cells as well as non-transformed murine embryonic fibroblasts with heterozygous or homozygous p53 deletion, and in freshly isolated thymocytes from mice with differential p53 status. These results expand the tumour-suppressive functions of p53 with an ex-ante activity that prevents DNA damage during replication. MDM2, target gene and main negative regulator of p53, acts to support DNA replication downstream of p53. In particular, its RING finger domain with intrinsic E3 ubiquitin ligase activity is required for this non-canonical role of MDM2. We demonstrated a mechanism by which MDM2 and its interaction partners of the Polycomb repressor complexes which mediate changes in chromatin compaction, prevent the formation of R-loops on the DNA template that impair replication progression. The p53-MDM2 axis helps to protect the genome during S phase, by preventing R-loops and hence enhancing replication. Clinically, our study highlights the importance of small molecule inhibitors against MDM2 that inhibit its RING domain on top of inhibitors targeting its interaction with p53 currently evaluated in clinical trials. We propose that the dual inhibition of both these domains of MDM2 using combination treatments would present a more promising chemotherapeutic strategy. de
dc.contributor.coReferee Shcherbata, Halyna PD Dr.
dc.subject.eng p53 de
dc.subject.eng Mdm2 de
dc.subject.eng Polycomb repressor complex de
dc.subject.eng ubiquitination de
dc.subject.eng histone de
dc.subject.eng RNF2 de
dc.subject.eng DNA replication de
dc.subject.eng R-loops de
dc.identifier.urn urn:nbn:de:gbv:7-11858/00-1735-0000-002E-E50B-5-6
dc.affiliation.institute Biologische Fakultät für Biologie und Psychologie de
dc.subject.gokfull Biologie (PPN619462639) de
dc.identifier.ppn 104082644X

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