Bolgi, Oguz ORCID: 0000-0003-0653-7530, Silva-Garcia, Maria, Ross, Breyan, Pilla, Esther, Kari, Vijayalakshmi, Killisch, Markus, Spitzner, Melanie, Stark, Nadine, Lenz, Christof ORCID: 0000-0002-0946-8166, Weiss, Konstantin, Donzelli, Laura ORCID: 0000-0001-5617-5297, Gorrell, Mark D., Grade, Marian, Riemer, Jan, Urlaub, Henning, Dobbelstein, Matthias ORCID: 0000-0001-5052-3967, Huber, Robert and Geiss-Friedlander, Ruth ORCID: 0000-0002-1720-3440 (2022). Dipeptidyl peptidase 9 triggers BRCA2 degradation and promotes DNA damage repair. EMBO Rep., 23 (10). HOBOKEN: WILEY. ISSN 1469-3178

Full text not available from this repository.

Abstract

N-terminal sequences are important sites for post-translational modifications that alter protein localization, activity, and stability. Dipeptidyl peptidase 9 (DPP9) is a serine aminopeptidase with the rare ability to cleave off N-terminal dipeptides with imino acid proline in the second position. Here, we identify the tumor-suppressor BRCA2 as a DPP9 substrate and show this interaction to be induced by DNA damage. We present crystallographic structures documenting intracrystalline enzymatic activity of DPP9, with the N-terminal Met1-Pro2 of a BRCA21-40 peptide captured in its active site. Intriguingly, DPP9-depleted cells are hypersensitive to genotoxic agents and are impaired in the repair of DNA double-strand breaks by homologous recombination. Mechanistically, DPP9 targets BRCA2 for degradation and promotes the formation of RAD51 foci, the downstream function of BRCA2. N-terminal truncation mutants of BRCA2 that mimic a DPP9 product phenocopy reduced BRCA2 stability and rescue RAD51 foci formation in DPP9-deficient cells. Taken together, we present DPP9 as a regulator of BRCA2 stability and propose that by fine-tuning the cellular concentrations of BRCA2, DPP9 alters the BRCA2 interactome, providing a possible explanation for DPP9's role in cancer.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bolgi, OguzUNSPECIFIEDorcid.org/0000-0003-0653-7530UNSPECIFIED
Silva-Garcia, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ross, BreyanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pilla, EstherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kari, VijayalakshmiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Killisch, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spitzner, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stark, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lenz, ChristofUNSPECIFIEDorcid.org/0000-0002-0946-8166UNSPECIFIED
Weiss, KonstantinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Donzelli, LauraUNSPECIFIEDorcid.org/0000-0001-5617-5297UNSPECIFIED
Gorrell, Mark D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grade, MarianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riemer, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Urlaub, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dobbelstein, MatthiasUNSPECIFIEDorcid.org/0000-0001-5052-3967UNSPECIFIED
Huber, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geiss-Friedlander, RuthUNSPECIFIEDorcid.org/0000-0002-1720-3440UNSPECIFIED
URN: urn:nbn:de:hbz:38-690747
DOI: 10.15252/embr.202154136
Journal or Publication Title: EMBO Rep.
Volume: 23
Number: 10
Date: 2022
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1469-3178
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HOMOLOGY-DIRECTED REPAIR; N-TERMINAL ACETYLATION; END RULE PATHWAY; RAD51 FILAMENT FORMATION; CROSS-LINK REPAIR; E3 LIGASE RFWD3; PROTEIN-FRAGMENTS; CELLULAR-PROTEINS; POOR-PROGNOSIS; IN-VIVOMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69074

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item