Genome stability is essential for cellular viability and tumour suppression. This stability is constantly under pressure from replication errors and diverse toxic stressors. DNA mismatch repair (MMR) is essential to correct replication errors. Defects in MMR lead to microsatellite instability (MSI), hypermutation, and predisposition to cancers such as Lynch syndrome, and strongly influence cellular responses to chemotherapeutics whose cytotoxicity depends on functional MMR. Despite extensive characterization of the protein factors that drive MMR, the contribution of non-protein regulators has remained largely unexplored.
One emerging area of interest is nuclear phosphoinositide signalling. In this study led by Xinyi Li in the Rubinsztein lab, nuclear phosphatidylinositol-3-phosphate (PI3P) is identified as a lipid regulator of MMR. PI3P forms discrete nuclear puncta in close proximity to the MutSα) and MutSβ MMR recognition complexes. Pharmacological or genetic depletion of the class III PI3-kinase Vps34 impaired MutSα and MutSβ heterodimer assembly without altering MMR protein nuclear abundance; compromised DNA substrate association of MMR components in nuclear extracts; and elevated microsatellite instability at mononucleotide repeats. Exogenous PI3P enhanced MMR recognition complex assembly and DNA association in PI3P-deficient nuclear extracts, supporting a role for PI3P in promoting MMR.
Collectively, these findings position nuclear PI3P as a lipid regulator of MMR, reveal a previously unrecognized autophagy-independent role of the Beclin-1/Vps34 complex, and highlight the broader relevance of nuclear phosphoinositide signalling in safeguarding genome integrity.