Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.24.265033v1?rss=1 Authors: Silva-Garcia, M., Bolgi, O., Ross, B., Pilla, E., Vijayalakshmi, K., Killisch, M., Stark, N., Lenz, C., Spitzner, M., Gorrell, M. D., Grade, M., Urlaub, H., Dobbelstein, M., Huber, R., Geiss-Friedlander, R. 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. Copy rights belong to original authors. Visit the link for more info