For the roughly 5–10% of breast and ovarian cancers driven by BRCA1 loss, finding drugs that selectively kill deficient cells while sparing healthy ones remains a central challenge in oncology. New structural and mechanistic work now clarifies how a DNA-repair enzyme called USP1 governs this vulnerability — and how tumors may eventually escape it.
The research centers on proliferating cell nuclear antigen (PCNA), a ring-shaped protein that acts as a sliding clamp on DNA replication forks. When DNA is damaged, the RAD6–RAD18 enzyme complex tags PCNA with a single ubiquitin molecule, activating a bypass pathway called translesion synthesis. A second round of K48-linked poly-ubiquitination then flags PCNA for proteasomal destruction. USP1 normally erases both ubiquitin marks, keeping PCNA stable. Using computational docking and cryo-structural analysis, the investigators identified a previously uncharacterized PCNA-interacting peptide (PIP) motif within RAD18 that is essential for this entire cascade. Mutating this interface abolishes damage-induced PCNA ubiquitination, prevents the accumulation of single-stranded DNA gaps at replication forks, and — critically — abolishes the synthetic lethality that USP1 inhibitors display in BRCA1-deficient cells. The team also found that cells chronically exposed to USP1 inhibitors downregulate RAD18 protein levels as an adaptive resistance mechanism, but that co-inhibiting the ATR kinase restores drug sensitivity.
This work is mechanistically precise and fills a genuine gap: the RAD18–PCNA binding interface had remained structurally undefined despite years of study. Placing it in the context of synthetic lethality adds direct translational relevance, particularly as USP1 inhibitors like KSQ-4279 enter early clinical trials. The RAD18-downregulation resistance pathway is a notable and clinically actionable discovery, though the findings derive from cell-line models and preprint data have not yet undergone peer review. Whether this resistance mechanism operates in patient tumors exposed to USP1 inhibitors in vivo remains to be established. Overall, this is an incremental but structurally important advance that meaningfully refines the mechanistic framework underlying a promising class of cancer drugs.