Related Experiment Video

Updated: Jul 15, 2026

Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
10:24

Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins

Published on: September 28, 2012

Nuclear PI3P produced by the Beclin-1/Vps34 complex regulates DNA mismatch repair

Xinyi Li1,2, Mariella Vicinanza1, Ana Lopez1,2,3

  • 1Cambridge Institute for Medical Research (CIMR), Department of Genomic Medicine, University of Cambridge, Cambridge CB2 0XY, United Kingdom.

Nucleic Acids Research
|July 14, 2026
PubMed

Insights

Nuclear phosphatidylinositol-3-phosphate (PI3P) regulates DNA mismatch repair (MMR) by promoting the assembly and DNA binding of MMR complexes. This lipid mediator, produced by a nuclear Beclin-1/Vps34 complex, is crucial for genome maintenance.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Genome integrity is maintained by DNA mismatch repair (MMR) to correct replication errors.
  • The role of non-protein cofactors in regulating MMR remains largely unexplored.
  • Nuclear phosphoinositide signaling is critical for various cellular processes.

Purpose of the Study:

  • To investigate the potential role of nuclear lipids as regulators of the DNA mismatch repair (MMR) pathway.
  • To identify specific lipids involved in MMR complex assembly and function.
  • To elucidate the mechanism by which nuclear lipids influence MMR activity and genome stability.

Main Methods:

  • Utilized biosensors, lipid pulldown assays, and proximity ligation assays to detect and characterize nuclear PI3P.
  • Employed pharmacological and genetic approaches to deplete the class III PI3-kinase Vps34.
  • Assessed MMR component assembly, DNA substrate association, and microsatellite instability.
  • Investigated the role of the Beclin-1/Vps34 complex in nuclear PI3P production.
  • Evaluated MMR-dependent DNA damage signaling and drug resistance in cellular and in vivo models.

Main Results:

  • Identified nuclear phosphatidylinositol-3-phosphate (PI3P) as a key regulator of MMR.
  • Demonstrated that PI3P localizes near MutSα (MSH2:MSH6) and MutSβ (MSH2:MSH3) complexes.
  • Showed that Vps34 depletion impairs MMR complex assembly and DNA association, leading to increased microsatellite instability.
  • Exogenous PI3P restored MMR function in PI3P-deficient extracts.
  • Revealed an autophagy-independent nuclear function for the Beclin-1/Vps34 complex in producing PI3P for MMR.
  • Loss of nuclear PI3P impaired DNA damage signaling and conferred drug resistance.

Conclusions:

  • Nuclear PI3P acts as a critical lipid mediator that promotes the assembly and DNA association of MMR recognition complexes.
  • The Beclin-1/Vps34 complex generates nuclear PI3P through an autophagy-independent mechanism, contributing to genome maintenance.
  • This study expands the known functions of nuclear phosphoinositide signaling and identifies a novel regulatory mechanism for MMR crucial for genome stability.

More Related Videos

Visualization of DNA Repair Proteins Interaction by Immunofluorescence07:55

Visualization of DNA Repair Proteins Interaction by Immunofluorescence

Published on: June 26, 2020

Advanced Confocal Microscopy Techniques to Study Protein-protein Interactions and Kinetics at DNA Lesions12:43

Advanced Confocal Microscopy Techniques to Study Protein-protein Interactions and Kinetics at DNA Lesions

Published on: November 12, 2017

Related Concept Videos

Mismatch Repair01:20

Mismatch Repair

Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
Mismatch Repair01:36

Mismatch Repair

Overview
Mismatch Repair01:36

Mismatch Repair

Overview
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
Homologous Recombination02:31

Homologous Recombination

The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...