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

Abstract

Summary 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.

Crystal Structure of the Werner’s Syndrome Helicase

“…This indicates on-target WRN knockdown and efficient transgenic complementation ( Figure 1C). Consistent with previous reports (19)(20)(21)27), the WRNr E84A transgene also successfully rescued the WRN depletion viability phenotype ( Figure 1C). Crucially, both the Walker A mutation K577M and the Walker B mutation E669A abrogated the WRNr transgene-mediated rescue of cell viability upon depletion of endogenous WRN ( Figure 1C).…”

“…Previous studies (19)(20)(21)27) demonstrated that WRN depletion causes pervasive DNA damage and the loss of viability selectively in MSI-H but not MSS cell lines. Mutational analyses of WRN suggested that ATP-binding of the helicase domain but not enzymatic activity of the exonuclease domain is critical for the survival of MSI-H cells.…”

“…Despite the emerging picture of WRN as a general maintainer of genome integrity and cancer suppressor, several recent studies have demonstrated a strong synthetic lethal relationship between WRN helicase and Microsatellite Instability-High (MSI-H) cancers (19)(20)(21). MSI-H cancers constitute a subset of colorectal, endometrial and gastric cancers that have deficiencies in the mismatch repair pathway and exhibit hyper-mutable state of microsatellite repeats.…”

Patient-Derived Xenografts and Matched Cell Lines Identify Pharmacogenomic Vulnerabilities in Colorectal Cancer

“…We have exploited our XL collection to assess if WRN dependency, which has been recently reported as a new synthetic lethality trait in MSI-H cancers (51)(52)(53)(54), could also apply to MSI-like colorectal tumors. MSI-like CRC models are genetically MSS, but bear intrinsic transcriptional features that resemble MSI-H cancers (55).…”

History of DNA Helicases

“…Since then, many papers describing synthetic lethal interactions of DNA helicases have appeared in the literature suggesting a general theme that helicases respond to replication stress via extended networks with numerous genetic interactions (for examples, see [267][268][269][270]). The recent identification of WRN helicase (mutated in Werner syndrome (WS), see below) as a synthetic lethal gene in microsatellite unstable cancers with defects in DNA MMR genes emphasizes the point [271][272][273][274]. The challenge in functional genomics remains to understand how, and in what context, certain DNA helicases have unique pathway functions.…”