PXD037263

PXD037263 is an original dataset announced via ProteomeXchange.

Title	The dimeric deubiquitinase Usp28 integrates 53bp1 and Myc functions to limit DNA damage
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:13:54.340.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Elias Einig
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-10-10 07:55:51	ID requested
1	2023-11-09 01:19:13	announced
⏵ 2	2024-10-22 06:13:54	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Human, AP-MS, Immunoprecipitation, USP28, 53BP1

Nikita Popov
contact affiliation	Medical Oncology and Pulmonology, University Hospital Tübingen, Otfried-Müller Straße 14, 72076 Tübingen, Germany
contact email	nbpopov@gmail.com
lab head
Elias Einig
contact affiliation	Medical Oncology and Pulmonology, University Hospital Tübingen, Germany
contact email	einig.elias@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD037263
     1. Label: PRIDE project
     2. Name: The dimeric deubiquitinase Usp28 integrates 53bp1 and Myc functions to limit DNA damage