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Proline-specific aminopeptidase P prevents replication-associated genome instability
Nicola Silva1,2, Maikel Castellano-Pozo1, Kenichiro Matsuzaki3
1Medical Research Council London Institute of Medical Sciences, London, United Kingdom.
Plos Genetics
|January 26, 2022
Summary
Aminopeptidase P (APP1) prevents genome instability during DNA replication. APP1 deficiency causes replication defects and DNA breaks, but not impaired DNA repair, highlighting its role in maintaining genome integrity.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Genotoxic stress during DNA replication threatens genome integrity and causes disease.
- While DNA metabolism defects cause replication stress, the role of other cellular metabolism aspects is unclear.
Purpose of the Study:
- To investigate the role of aminopeptidase P (APP1) in preventing replication-associated genome instability.
- To understand the relationship between protein catabolism and DNA replication.
Main Methods:
- Functional analysis of C. elegans mutants lacking APP-1.
- Assessing DNA double-strand break (DSB) repair capacity after gamma irradiation and in SPO-11 dependent DSBs.
- Depletion of APP1 (XPNPEP1) in mitotically-proliferating human cells.
Main Results:
- C. elegans app-1 mutants exhibit replication defects (reduced proliferation, cell cycle arrest, mitotic DSBs).
- app-1 mutants efficiently repair DSBs from irradiation and meiosis initiation, and spontaneous DSBs are repaired as crossovers.
- APP1 depletion in human cells also leads to DSB accumulation, indicating conserved function.
Conclusions:
- APP1 prevents replication stress and maintains genome stability.
- APP1's role in genome stability is evolutionarily conserved from C. elegans to humans.
- This study reveals a novel connection between aminopeptidase-mediated protein catabolism and DNA replication.
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