WRN Is a Promising Synthetic Lethal Target for Cancers with Microsatellite Instability (MSI)

Area of Science:

• Genetics
• Cancer Biology
• Molecular Oncology

Background:

• Microsatellite instability (MSI) is a genetic hallmark of approximately 3% of human cancers, stemming from deficient DNA mismatch repair (MMR).
• The RecQ helicase WRN has emerged as a potential synthetic lethal target in MSI cancers based on preclinical findings.

Purpose of the Study:

• To investigate the mechanism underlying the synthetic lethality observed upon WRN depletion in MSI cancer cells.
• To elucidate the role of TA dinucleotide repeat expansions in driving this synthetic lethal phenotype.

Main Methods:

• Depletion of WRN protein in MSI and microsatellite stable (MSS) cancer cell lines.
• Analysis of cell viability and DNA replication fork dynamics.
• Assessment of TA dinucleotide repeat length and secondary DNA structure formation.

Main Results:

• WRN depletion significantly reduced the viability of MSI cells but had minimal impact on MSS cells.
• MSI cells exhibited an increased accumulation of expanded TA dinucleotide repeats.
• These expanded repeats were found to form secondary DNA structures that are dependent on WRN for resolution.
• In the absence of WRN, unresolved DNA secondary structures led to stalled replication forks and DNA damage.

Conclusions:

• The synthetic lethal interaction between WRN depletion and MSI is driven by the accumulation of expanded TA repeats.
• WRN is crucial for resolving secondary DNA structures formed by these repeats in MSI cells, thereby preventing replication stress and genomic instability.