The dimeric deubiquitinase Usp28 integrates 53bp1 and Myc functions to limit DNA damage

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dc.contributor.advisor Ewald, Jennifer (Prof. Dr.)
dc.contributor.author Jin, Chao
dc.date.accessioned 2023-11-14T14:29:54Z
dc.date.available 2023-11-14T14:29:54Z
dc.date.issued 2023-11-14
dc.identifier.uri http://hdl.handle.net/10900/147756
dc.identifier.uri http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1477568 de_DE
dc.identifier.uri http://dx.doi.org/10.15496/publikation-89097
dc.description.abstract Myc is an important transcription factor that regulates a series of cellular functions. It is also well-known as an oncoprotein, as it is frequently dysregulated in more than half of all human cancers. The ubiquitin system regulates the biological functions of Myc. For example, ubiquitination controls the recruitment of the elongation factor Paf1c1, which is critical for Myc activity. Usp28 was identified as a deubiquitinase of Myc that can stabilize it from proteasomal degradation by removing ubiquitin. Usp28 is known to form homodimers in vitro and in cells, but the biological role of Usp28 dimerization is unknown. In this thesis, we showed that Usp28 can regulate Myc stability and Myc-driven transcription in the human liver cancer cell line HLF. Monomeric Usp28 shows enhanced deubiquitination activity towards Myc and facilitates Paf1c recruitment on Myc, but with no transcriptional effect. In contrast, the reinforced Paf1c-Myc binding by Usp28 monomers leads to decreased transcription-replication conflicts and stimulates DNA replication, which further accumulates replication-associated DNA damage. We further showed that the dimerization of Usp28 is regulated by 53bp1, a known substrate of Usp28 that plays an important role in DNA damage response. 53bp1 can specifically bind to dimeric Usp28, and genotoxic stress disrupts Usp28's association with 53bp1, which promotes the formation of Usp28 monomers and enhances the recruitment of Paf1c by Myc. This triggers ectopic DNA synthesis during the early response to genotoxins, amplifying DNA replication-associated DNA double-strand breaks. We then tested different cell lines with several different DNA damage inducers to show that this transient effect is universal in the multicellular context. The inhibition of DNA replication concomitantly with genotoxin treatment reduces DNA damage and promotes cell viability, indicating that the stabilization of Myc and acute DNA replication are early pathological effects of genotoxic stress rather than a programmed rescue mechanism. Overall, our results provide a simple but reasonable explanation of the activation of Usp28 upon DNA damage and we therefore propose a model that dimerization of Usp28 limits aberrant replication at transcriptionally active chromatin to maintain genome stability. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en en
dc.subject.classification DNS-Schädigung , Myc , Ubiquitinierung , Replikation de_DE
dc.subject.ddc 000 de_DE
dc.subject.ddc 500 de_DE
dc.subject.ddc 570 de_DE
dc.subject.ddc 610 de_DE
dc.subject.other Usp28 en
dc.subject.other DNA damage response en
dc.title The dimeric deubiquitinase Usp28 integrates 53bp1 and Myc functions to limit DNA damage en
dc.type PhDThesis de_DE
dcterms.dateAccepted 2023-11-07
utue.publikation.fachbereich Biologie de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE
utue.publikation.noppn yes de_DE

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