Dipeptidyl peptidase 9 triggers BRCA2 degradation and promotes DNA damage repair
Abstract: 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
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Anmerkungen
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EMBO reports. - 23, 10 (2022) , e54136, ISSN: 1469-3178
- Ereignis
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Veröffentlichung
- (wo)
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Freiburg
- (wer)
-
Universität
- (wann)
-
2022
- Urheber
-
Bolgi, Oğuz
Silva Garcia, Maria
Ross, Breyan
Pilla, Esther
Kari, Vijayalakshmi
Killisch, Markus
Spitzner, Melanie
Stark, Nadine
Lenz, Christof
Weiss, Konstantin
Donzelli, Laura
Gorrell, Mark D.
Grade, Marian
Riemer, Jan
Urlaub, Henning
Dobbelstein, Matthias
Huber, Robert
Geiss-Friedlander, Ruth
- DOI
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10.15252/embr.202154136
- URN
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urn:nbn:de:bsz:25-freidok-2290036
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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25.03.2025, 13:46 MEZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- Bolgi, Oğuz
- Silva Garcia, Maria
- Ross, Breyan
- Pilla, Esther
- Kari, Vijayalakshmi
- Killisch, Markus
- Spitzner, Melanie
- Stark, Nadine
- Lenz, Christof
- Weiss, Konstantin
- Donzelli, Laura
- Gorrell, Mark D.
- Grade, Marian
- Riemer, Jan
- Urlaub, Henning
- Dobbelstein, Matthias
- Huber, Robert
- Geiss-Friedlander, Ruth
- Universität
Entstanden
- 2022
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