Repeat expansions confer WRN dependence in microsatellite-unstable cancers

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• Microsatellite instability (MSI) cancers exhibit genetic hypermutability due to impaired DNA mismatch repair.
• The RecQ DNA helicase WRN is a synthetic lethal target in MSI cancers, but its protective mechanism is unclear.
• WRN depletion causes DNA double-strand breaks, cell cycle arrest, and apoptosis in MSI cells.

Purpose of the Study:

• To elucidate the mechanism by which WRN protects MSI-associated cancers from DNA double-strand breaks.
• To identify the role of TA-dinucleotide repeats in WRN's function in MSI cells.
• To establish WRN as a therapeutic target for MSI cancers.

Main Methods:

• Analysis of TA-dinucleotide repeat instability in MSI cells.
• Investigation of non-B DNA secondary structure formation by expanded TA repeats.
• Assessment of replication fork stalling and ATR checkpoint activation.
• Evaluation of WRN helicase activity and MUS81 nuclease cleavage in the absence of WRN.

Main Results:

• TA-dinucleotide repeats are highly unstable in MSI cells, undergoing large-scale expansions.
• Expanded TA repeats form non-B DNA structures that stall replication forks and activate ATR.
• WRN helicase unwinds expanded TA repeats, preventing replication fork collapse.
• Absence of WRN leads to MUS81-mediated cleavage of expanded TA repeats and chromosome shattering.

Conclusions:

• Expanded TA-dinucleotide repeats are a distinct biomarker for synthetic lethality in WRN-deficient MSI cancers.
• WRN is crucial for resolving replication stress induced by expanded TA repeats in MSI cells.
• Targeting WRN offers a therapeutic strategy for MSI-associated cancers.