Proline-specific aminopeptidase P prevents
replication-associated genome instability

J 2022

Proline-specific aminopeptidase P prevents replication-associated genome instability

SILVA, Nicola, Maikel CASTELLANO-POZO, Kenichiro J. MATSUZAKI, Consuelo BARROSO, Monica P. ROMAN-TRUFERO et. al.

Basic information

Original name

Proline-specific aminopeptidase P prevents replication-associated genome instability

Authors

SILVA, Nicola (380 Italy, belonging to the institution), Maikel CASTELLANO-POZO, Kenichiro J. MATSUZAKI, Consuelo BARROSO, Monica P. ROMAN-TRUFERO, Hannah CRAIG, Darren P. BROOKS, R. Elwyn ISAAC, Simon P. BOULTON and Enrique MARTINEZ-PEREZ (guarantor)

Edition

PLoS Genetics, San Francisco, Public Library of Science, 2022, 1553-7404

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10603 Genetics and heredity

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 4.500

RIV identification code

RIV/00216224:14110/22:00128227

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1371/journal.pgen.1010025

UT WoS

000748003200001

Keywords in English

Proline-specific aminopeptidase P; replication-associated genome instability

Abstract

V originále

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. Author summaryThe accurate duplication of DNA that occurs before cells divide is an essential aspect of the cell cycle that is also crucial for the correct development of multicellular organisms. Mutations that compromise the normal function of the DNA replication machinery can lead to the accumulation of replication-related DNA damage, a known cause of human disease and a common feature of cancer and precancerous cells. Therefore, identifying factors that prevent replication-related DNA damage is highly relevant for human health. In this manuscript, we identify aminopeptidase P, an enzyme involved in the breakdown of proteins containing the amino acid Proline at their N-terminus, as a novel factor that prevents replication-related DNA damage. Analysis of C. elegans nematodes lacking aminopeptidase P reveals that this protein is required for normal fertility and development, and that in its absence proliferating germ cells display DNA replication defects, including cell cycle arrest and accumulation of extensive DNA damage. We also show that removal of aminopeptidase P induces DNA damage in proliferating human cells, suggesting that its role in preventing replication defects is evolutionarily conserved. These findings uncover functional connections between aminopeptidase-mediated protein degradation and DNA replication.

Links

GA20-08819S, research and development project

Name: Pochopení úlohy PARG při podpoře tvorby a oprav dvouřetězcových zlomů DNA v meióze

Investor: Czech Science Foundation

MUNI/A/1418/2021, interní kód MU

Name: Biomedicínské vědy II (Acronym: BIOMED)

Investor: Masaryk University

Citovat

SILVA, Nicola, Maikel CASTELLANO-POZO, Kenichiro J. MATSUZAKI, Consuelo BARROSO, Monica P. ROMAN-TRUFERO, Hannah CRAIG, Darren P. BROOKS, R. Elwyn ISAAC, Simon P. BOULTON and Enrique MARTINEZ-PEREZ. Proline-specific aminopeptidase P prevents replication-associated genome instability. PLoS Genetics. San Francisco: Public Library of Science, 2022, vol. 18, No 1, p. 1-25. ISSN 1553-7404. Available from: https://dx.doi.org/10.1371/journal.pgen.1010025.

@article{2249120,
   author = {Silva, Nicola and CastellanoandPozo, Maikel and Matsuzaki, Kenichiro J. and Barroso, Consuelo and RomanandTrufero, Monica P. and Craig, Hannah and Brooks, Darren P. and Isaac, R. Elwyn and Boulton, Simon P. and MartinezandPerez, Enrique},
   article_location = {San Francisco},
   article_number = {1},
   doi = {http://dx.doi.org/10.1371/journal.pgen.1010025},
   keywords = {Proline-specific aminopeptidase P; replication-associated genome instability},
   language = {eng},
   issn = {1553-7404},
   journal = {PLoS Genetics},
   title = {Proline-specific aminopeptidase P prevents replication-associated genome instability},
   url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010025},
   volume = {18},
   year = {2022}
}

TY  - JOUR
ID  - 2249120
AU  - Silva, Nicola - Castellano-Pozo, Maikel - Matsuzaki, Kenichiro J. - Barroso, Consuelo - Roman-Trufero, Monica P. - Craig, Hannah - Brooks, Darren P. - Isaac, R. Elwyn - Boulton, Simon P. - Martinez-Perez, Enrique
PY  - 2022
TI  - Proline-specific aminopeptidase P prevents replication-associated genome instability
JF  - PLoS Genetics
VL  - 18
IS  - 1
SP  - 1-25
EP  - 1-25
PB  - Public Library of Science
SN  - 15537404
KW  - Proline-specific aminopeptidase P
KW  - replication-associated genome instability
UR  - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010025
N2  - 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. Author summaryThe accurate duplication of DNA that occurs before cells divide is an essential aspect of the cell cycle that is also crucial for the correct development of multicellular organisms. Mutations that compromise the normal function of the DNA replication machinery can lead to the accumulation of replication-related DNA damage, a known cause of human disease and a common feature of cancer and precancerous cells. Therefore, identifying factors that prevent replication-related DNA damage is highly relevant for human health. In this manuscript, we identify aminopeptidase P, an enzyme involved in the breakdown of proteins containing the amino acid Proline at their N-terminus, as a novel factor that prevents replication-related DNA damage. Analysis of C. elegans nematodes lacking aminopeptidase P reveals that this protein is required for normal fertility and development, and that in its absence proliferating germ cells display DNA replication defects, including cell cycle arrest and accumulation of extensive DNA damage. We also show that removal of aminopeptidase P induces DNA damage in proliferating human cells, suggesting that its role in preventing replication defects is evolutionarily conserved. These findings uncover functional connections between aminopeptidase-mediated protein degradation and DNA replication.
ER  -

SILVA, Nicola, Maikel CASTELLANO-POZO, Kenichiro J. MATSUZAKI, Consuelo BARROSO, Monica P. ROMAN-TRUFERO, Hannah CRAIG, Darren P. BROOKS, R. Elwyn ISAAC, Simon P. BOULTON and Enrique MARTINEZ-PEREZ. Proline-specific aminopeptidase P prevents replication-associated genome instability. \textit{PLoS Genetics}. San Francisco: Public Library of Science, 2022, vol.~18, No~1, p.~1-25. ISSN~1553-7404. Available from: https://dx.doi.org/10.1371/journal.pgen.1010025.

Detailed Information on Publication Record