Elevated MSH2 MSH3 expression interferes with DNA metabolism in vivo

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• The Msh2-Msh3 mismatch repair (MMR) complex in Saccharomyces cerevisiae plays a dual role in genome stability.
• It repairs insertion/deletion loops (IDLs) and interacts with various DNA structures, influencing homologous recombination and DNA damage response.
• However, Msh2-Msh3 can also promote genome instability, particularly through trinucleotide repeat (TNR) expansions.

Purpose of the Study:

• To investigate the in vivo consequences of elevated Msh2-Msh3 levels on DNA replication and repair.
• To elucidate the mechanistic details underlying Msh2-Msh3-mediated genomic instability.
• To determine the role of Msh2-Msh3 abundance and activity in these processes.

Main Methods:

• In vivo studies in Saccharomyces cerevisiae assessing DNA replication and base excision repair.
• Analysis of cell cycle arrest phenotypes, including dependence on RAD9 and ELG1, and PCNA modification.
• Investigation of the requirement for Msh2-Msh3 ATPase activity and downstream MMR proteins.

Main Results:

• Elevated Msh2-Msh3 levels interfere with DNA replication and base excision repair in vivo.
• Increased Msh2-Msh3 induced a cell cycle arrest dependent on RAD9 and ELG1, and caused PCNA modification.
• These effects were dependent on Msh2-Msh3 ATPase activity and downstream MMR proteins, indicating an active disruption mechanism.

Conclusions:

• Excess Msh2-Msh3 actively disrupts DNA replication and repair pathways.
• Msh2-Msh3 protein abundance is a critical factor in Msh2-Msh3-mediated genomic instability.
• This study provides new mechanistic insights into how MMR complex levels impact genome stability.