Bolgi_2022_EMBO.Rep__e54136

Reference

Title : Dipeptidyl peptidase 9 triggers BRCA2 degradation and promotes DNA damage repair - Bolgi_2022_EMBO.Rep__e54136
Author(s) : Bolgi O , Silva-Garcia M , Ross B , Pilla E , Kari V , Killisch M , Spitzner M , Stark N , Lenz C , Weiss K , Donzelli L , Gorrell MD , Grade M , Riemer J , Urlaub H , Dobbelstein M , Huber R , Geiss-Friedlander R
Ref : EMBO Rep , :e54136 , 2022
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.

PubMedSearch : Bolgi_2022_EMBO.Rep__e54136
PubMedID: 35912982
Gene_locus related to this paper: human-DPP8 , human-DPP9

Related information

Gene_locus human-DPP8    human-DPP9
Structure human-DPP8    human-DPP9    6QZW    6QZV

Citations formats

Bolgi O, Silva-Garcia M, Ross B, Pilla E, Kari V, Killisch M, Spitzner M, Stark N, Lenz C, Weiss K, Donzelli L, Gorrell MD, Grade M, Riemer J, Urlaub H, Dobbelstein M, Huber R, Geiss-Friedlander R (2022)
Dipeptidyl peptidase 9 triggers BRCA2 degradation and promotes DNA damage repair
EMBO Rep :e54136

Bolgi O, Silva-Garcia M, Ross B, Pilla E, Kari V, Killisch M, Spitzner M, Stark N, Lenz C, Weiss K, Donzelli L, Gorrell MD, Grade M, Riemer J, Urlaub H, Dobbelstein M, Huber R, Geiss-Friedlander R (2022)
EMBO Rep :e54136