Silva-Garcia_2020_Biorxiv__

Reference

Title : Dipeptidyl peptidase 9 triggers BRCA2 degradation by the N-degron pathway to promote DNA-damage repair - Silva-Garcia_2020_Biorxiv__
Author(s) : Silva-Garcia M , Bolgi O , Ross B , Pilla E , Kari V , Killisch M , Stark N , Lenz C , Spitzner M , Gorrell MD , Grade M , Urlaub H , Dobbelstein M , Huber R , Geiss-Friedlander R
Ref : Biorxiv , : , 2020
Abstract :

Dipeptidyl peptidase 9 (DPP9) is a serine protease cleaving N-terminal dipeptides preferentially post-proline with (patho)physiological roles in the immune system and cancer. Only few DPP9 substrates are known. Here we identify an association of human DPP9 with the tumour suppressor BRCA2, a key player in repair of DNA double-strand breaks that promotes the formation of RAD51 filaments. This interaction is triggered by DNA-damage and requires access to the DPP9 active-site. We present crystallographic structures documenting the N-terminal Met1-Pro2 of a BRCA21-40 peptide captured in the DPP9 active-site. Mechanistically, DPP9 targets BRCA2 for degradation by the N-degron pathway, and promotes RAD51 foci formation. Both processes are phenocopied by BRCA2 N-terminal truncation mutants, indicating that DPP9 regulates both stability and the cellular stoichiometric interactome of BRCA2. Consistently, DPP9-deprived cells are hypersensitive to DNA-damage. Together, we identify DPP9 as a regulator of BRCA2, providing a possible explanation for DPP9 involvement in cancer development.

PubMedSearch : Silva-Garcia_2020_Biorxiv__
PubMedID:
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

Silva-Garcia M, Bolgi O, Ross B, Pilla E, Kari V, Killisch M, Stark N, Lenz C, Spitzner M, Gorrell MD, Grade M, Urlaub H, Dobbelstein M, Huber R, Geiss-Friedlander R (2020)
Dipeptidyl peptidase 9 triggers BRCA2 degradation by the N-degron pathway to promote DNA-damage repair
Biorxiv :

Silva-Garcia M, Bolgi O, Ross B, Pilla E, Kari V, Killisch M, Stark N, Lenz C, Spitzner M, Gorrell MD, Grade M, Urlaub H, Dobbelstein M, Huber R, Geiss-Friedlander R (2020)
Biorxiv :