Exploring the Potential of Homologous Recombination Protein PALB2 in Synthetic Lethal Combinations

TL;DR

This paper explores how targeting the PALB2 protein, involved in DNA repair, could lead to new cancer treatments by exploiting synthetic lethal interactions.

Contribution

The study introduces a model system using a degron in PALB2 and identifies a high-affinity peptide ligand for future drug development.

Findings

A model system was developed to study PARP/HR synthetic lethality using a zinc-finger degron in PALB2.

A high-affinity peptide ligand for PALB2 was identified, supporting future therapeutic development.

PALB2 is validated as a promising drug target for exploiting synthetic lethal interactions in cancer cells.

Abstract

Cells with defective homologous recombination (HR) are
highly sensitive
to poly(ADP-ribose) polymerase (PARP) inhibition. Current therapeutic
approaches leverage this vulnerability by using PARP inhibitors in
cells with genetically compromised HR. However, if HR factors in cancer
cells could be inhibited or degraded pharmacologically, it might reveal
other opportunities for synergistic combinations. In this study, we
developed a model system that recapitulates PARP/HR synthetic lethality
by integrating a small-molecule responsive zinc-finger degron into
the HR factor Partner and Localizer of BRCA2 (PALB2). We further tested
a series of peptide ligands for PALB2 based on its natural binding
partners, which led to the discovery of a high affinity peptide that
will support future work on PALB2 and HR. Together, our findings validate
PALB2 as a promising drug target and provide the tools and starting
points for developing molecules with therapeutic applications.

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