Proline-specific aminopeptidase P prevents replication-associated genome instability

Silva, N; Castellano-Pozo, M; Matsuzaki, K; Barroso, C; Roman-Trufero, M; Craig, H; Brooks, DR; Isaac, RE; Boulton, SJ; Martinez-Perez, E

Abstract

Genotoxic stress during DNA replication constitutes a serious threat to genome integrity and causes human diseases. Defects at different steps of DNA metabolism are known to induce replication stress, but the contribution of other aspects of cellular metabolism is less understood. We show that aminopeptidase P (APP1), a metalloprotease involved in the catabolism of peptides containing proline residues near their N-terminus, prevents replication-associated genome instability. Functional analysis of C. elegans mutants lacking APP-1 demonstrates that germ cells display replication defects including reduced proliferation, cell cycle arrest, and accumulation of mitotic DSBs. Despite these defects, app-1 mutants are competent in repairing DSBs induced by gamma irradiation, as well as SPO-11-dependent DSBs that initiate meiotic recombination. Moreover, in the absence of SPO-11, spontaneous DSBs arising in app-1 mutants are repaired as inter-homologue crossover events during meiosis, confirming that APP-1 is not required for homologous recombination. Thus, APP-1 prevents replication stress without having an apparent role in DSB repair. Depletion of APP1 (XPNPEP1) also causes DSB accumulation in mitotically-proliferating human cells, suggesting that APP1’s role in genome stability is evolutionarily conserved. Our findings uncover an unexpected role for APP1 in genome stability, suggesting functional connections between aminopeptidase-mediated protein catabolism and DNA replication.

Citation

Silva, N., Castellano-Pozo, M., Matsuzaki, K., Barroso, C., Roman-Trufero, M., Craig, H., …Martinez-Perez, E. (2022). Proline-specific aminopeptidase P prevents replication-associated genome instability. PLoS Genetics, 18(1), e1010025. https://doi.org/10.1371/journal.pgen.1010025

• Journal Article Type: Article
• Acceptance Date: Jan 10, 2022
• Online Publication Date: Jan 26, 2022
• Publication Date: Jan 26, 2022
• Deposit Date: Feb 8, 2022
• Publicly Available Date: Feb 8, 2022
• Journal: PLOS Genetics
• Print ISSN: 1553-7390
• Publisher: Public Library of Science
• Volume: 18
• Issue: 1
• Pages: e1010025
• DOI: https://doi.org/10.1371/journal.pgen.1010025
• Publisher URL: https://doi.org/10.1371/journal.pgen.1010025
• Related Public URLs: https://journals.plos.org/plosgenetics/
• Additional Information: Additional Information : ** From PLOS via Jisc Publications Router ** Licence for this article: http://creativecommons.org/licenses/by/4.0/ **Journal IDs: pissn 1553-7390; eissn 1553-7404 **Article IDs: publisher-id: pgenetics-d-21-01257 **History: published_online 26-01-2022; accepted 10-01-2022; collection 01-2022; submitted 17-09-2021; Funders : Grantová Agentura České Republiky;Department of Biology of Masaryk University;Biotechnology and Biosciences Sciences Research Council (BBSRC);Cancer Research UK;Francis Crick Institute;European Research Council;Medical Research Council (MRC);Biotechnology and Biological Sciences Research Council;Medical Research Council; Projects : GA20-08819S;24/S12813;unspecified;RecMitMei;David Phillips Fellowship;MC-A652-5PY60; Grant Number: GA20-08819S; Grant Number: 24/S12813; Grant Number: MC-A652-5PY60