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

ABSTRACT: The oncogenic transcription factor Myc is a pleiotropic regulator of RNA Polymerase II (RNAPII)-dependent transcription, DNA replication and DNA damage response pathways. Myc is stringently regulated by the ubiquitin system - for example, ubiquitination controls recruitment of the elongation factor Paf1c, which is critical for several Myc functions. Curiously, a key Myc-targeting deubiquitinase Usp28 also controls cellular response to DNA damage via the mediator protein 53bp1. Usp28 forms stable dimers, but the biological role of Usp28 dimerization is unknown. We show that dimerization limits Usp28 activity and restricts recruitment of Paf1c by Myc. Expression of monomeric Usp28 leads to ectopic Paf1c recruitment and resolution of transcription-replication conflicts, accelerating DNA synthesis. Strikingly, 53bp1 selectively interacts with and stabilizes dimeric Usp28 - depletion of 53bp1 favors formation of Usp28 monomers deregulating DNA replication. Genotoxic stress disrupts 53bp1-Usp28 complexes, promotes formation of Usp28 monomers and recruitment of Paf1 by Myc. This triggers ectopic DNA synthesis during early response to genotoxins, amplifying DNA damage. We propose that dimerization of Usp28 limits aberrant replication at transcriptionally active chromatin to maintain genome stability.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Elias Einig

LAB HEAD: Nikita Popov

PROVIDER: PXD037263 | Pride | 2023-11-09

REPOSITORIES: Pride

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