DNA polymerase

Cancer cell

Molecular biology

Cancer research

DNA mismatch repair

Microsatellite

DNA repair

Werner syndrome

DNA damage

Genome instability

Biology

Gene

Exonuclease

Cancer

Helicase

RecQ helicase

Allele

Microsatellite instability

Bloom syndrome

Genetics

iScience

Werner syndrome protein (WRN) is a RecQ enzyme involved in the maintenance of genome integrity. Germline loss-of-function mutations in WRN led to premature aging and predisposition to cancer. We evaluated synthetic lethal (SL) interactions between WRN and another human RecQ helicase, BLM, with DNA damage response genes in cancer cell lines. We found that WRN was SL with a DNA mismatch repair protein MutL homolog 1, loss of which is associated with high microsatellite instability (MSI-H). MSI-H cells exhibited increased double-stranded DNA breaks, altered cell cycles, and decreased viability in response to WRN knockdown, in contrast to microsatellite stable (MSS) lines, which tolerated depletion of WRN. Although WRN is the only human RecQ enzyme with a distinct exonuclease domain, only loss of helicase activity drives the MSI SL interaction. This SL interaction in MSI cancer cells positions WRN as a relevant therapeutic target in patients with MSI-H tumors.

Werner Syndrome Helicase Is Required for the Survival of Cancer Cells with Microsatellite Instability