Finding a way to shutdown rogue cell replication

24 July 2019:

Almost all cells replace themselves by replicating, but when there are errors in DNA-replication, it can lead to diseases including many cancers.

DNA-replication is complex and involves a host of protein machinery. One of the most important is the protein PCNA, which helps orchestrate the process.

Adelaide University postgraduate student Aimee Horsfall, a member of the ARC Centre of Excellence for Nanoscale Biophotonics (CNBP), was part of the team which analysed the structures of a number of proteins interacting with PCNA.

The work suggests that the 3D shape of these proteins defines how strongly this interaction occurs.

The research is important because, if we can understand what makes the interaction with PCNA stronger, and determine the optimal shape, we can develop a drug that mimics it.

This drug could bind PCNA and stop replication in diseased cells, offering a potential treatment for diseases implicated in erroneous DNA-replication, or as a broad spectrum cancer therapeutic.

Journal: ChemBioChem

Publication Title: Targeting PCNA with peptide mimetics for therapeutic purposes.

Authors: Horsfall AJ, Abell AD, Bruning J.

Abstract: PCNA is an excellent inhibition target to shut down highly proliferative cells and thereby develop a broad spectrum cancer therapeutic. It interacts with a wide variety of proteins through a conserved motif referred to as the PCNA-Interacting Protein (PIP) box. There is large sequence diversity between high affinity PCNA binding partners, with conservation of the binding structure – a well-defined 310-helix. Here, all current PIP-box peptides crystallised with human PCNA are collated to reveal common trends between binding structure and affinity. Key intra- and inter-molecular hydrogen bonding networks which stabilise the 310-helix of PIP-box partners are highlighted, and related back to the canonical PIP-box motif. High correlation with the canonical PIP-box sequence does not directly afford high affinity. Instead, we summarise key interactions which stabilise the binding structure that lead to enhanced PCNA binding affinity. These interactions also implicate the ‘non-conserved’ residues within the PIP-box that have previously been overlooked. Such insights will allow a more directed approach to develop therapeutic PCNA inhibitors.

Keywords: PCNA, peptide mimetics, PIP-box, sliding clamp, DNA replication

Link: https://www.ncbi.nlm.nih.gov/pubmed/31247123