Researchers from the MRC London Institute of Medical Sciences (LMS), Leeds University, and the Francis Crick Institute have shown for the first time that an enzyme called aminopeptidase-P (APP1) prevents DNA damage accumulation during DNA replication.

As DNA unwinds to replicate it exposes itself to cellular process and chemicals that can damage it. This occurrence is termed genotoxic stress. It is a serious threat to genome integrity, contributing to human disease.

Previous research has highlighted how defects in the DNA’s own metabolic processes can induce replication stress, leading to its damage. However, the extent to which other aspects of cellular metabolism contribute to genotoxic stress is less understood. To delve deeper into this, researchers from the LMS Meiosis research group teamed up with Elwyn Isaac’s group at Leeds University and the Crick’s Boulton laboratory.

Aminopeptidase P (APP1) is an enzyme involved in the breakdown of cellular proteins that carry  an amino acid called proline near the start of the protein. The team of researchers found germ cells in C. elegans worms lacking  APP1 displayed reduced cell proliferation and   extensive accumulation of DNA double strand breaks (DSBs),  the most toxic form of DNA damage if left unrepaired. However, most DSBs were eventually repaired in mutants lacking APP1, suggesting that APP1 is required to prevent the onset of DNA damage, rather than for its repair.

The researchers then went on to investigate the function of APP1 in human cells. They found that removing APP1 from proliferating human cells also induced accumulation of DNA damage, including DSBs, suggesting that the role of APP1 to protect genome integrity is conserved across evolution.

Dr Enrique (Fadri) Martinez-Perez, head of the LMS Meiosis research group said: “Our finding that APP1 prevents the onset of replication-related genome instability could have therapeutic potential, as inhibitors targeting proteins promoting normal progression of DNA replication are key components of chemotherapy protocols used to treat human malignancies.

“Our research also highlights how the powerful genetic toolkit of C. elegans can be exploited to investigate cellular processes relevant to human health”

Proline-specific aminopeptidase P prevents replication-associated genome instability was published in PLOS Genetics on 26 January 2022.