Academic Journal
CRISPR Screening Identifies SMARCAL1 and MRN as Modulators of WRN Dependency in MSI-H Colorectal Cancer.
| Τίτλος: | CRISPR Screening Identifies SMARCAL1 and MRN as Modulators of WRN Dependency in MSI-H Colorectal Cancer. |
|---|---|
| Συγγραφείς: | Ma T; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wu J; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Li S; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Chen J; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. |
| Πηγή: | Cancer research [Cancer Res] 2026 Oct 15; Vol. 86 (20), pp. 5271-5286. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE |
| Imprint Name(s): | Publication: Baltimore, Md. : American Association for Cancer Research Original Publication: Chicago [etc.] |
| Ιατρικοί όροι (MeSH): | Werner Syndrome Helicase*/genetics , Werner Syndrome Helicase*/metabolism , Werner Syndrome Helicase*/antagonists & inhibitors , Colorectal Neoplasms*/genetics , Colorectal Neoplasms*/metabolism , Colorectal Neoplasms*/pathology , DNA Helicases*/genetics , DNA Helicases*/metabolism , MRE11 Homologue Protein*/metabolism , MRE11 Homologue Protein*/genetics , Cell Cycle Proteins*/metabolism , Cell Cycle Proteins*/genetics , Nuclear Proteins*/metabolism , Nuclear Proteins*/genetics , DNA Repair Enzymes*/metabolism , DNA Repair Enzymes*/genetics , Microsatellite Instability*, DNA-Binding Proteins/metabolism ; DNA-Binding Proteins/genetics ; Humans ; Cell Line, Tumor ; CRISPR-Cas Systems ; Acid Anhydride Hydrolases |
| Περίληψη: | Microsatellite instability-high (MSI-H) colorectal cancer cells depend on the Werner syndrome helicase (WRN) to resolve cruciform DNA structures that arise from expanded TA-dinucleotide repeats. Loss of WRN induces replication stress and double-strand breaks, a vulnerability that can be recapitulated with the selective WRN inhibitor (WRNi) HRO761 in MSI-H cancer cells. To uncover the mechanisms governing sensitivity to WRN inhibition, we conducted genome-wide CRISPR/Cas9 screens in colorectal cancer cell lines treated with or without HRO761. These screens identified SMARCAL1 as a key modulator of WRN dependency. Depletion of SMARCAL1 rendered cells resistant to WRN inhibition, and rescue of this effect required the ATPase/translocase activity of SMARCAL1. Mechanistically, SMARCAL1 antagonized WRN and supported cruciform DNA structures, thereby enhancing cellular reliance on WRN. In addition, the MRE11-RAD50-NBS1 (MRN) complex, rather than MUS81 or ERCC1/XPF, was the principal mediator of cruciform DNA processing following WRN inhibition. Acute disruption of the MRN complex conferred profound resistance to WRN inhibition, whereas ataxia-telangiectasia mutated (ATM) deficiency produced a more modest resistant phenotype. Further genetic and pharmacologic epistasis analyses demonstrated that the MRN complex regulates WRNi sensitivity through both ATM-dependent signaling and MRE11 nuclease-dependent functions. Importantly, the key resistance mechanisms identified in this study were independently validated using a structurally distinct clinical-stage WRNi, VVD-214. Collectively, these findings identify the SMARCAL1-MRN-ATM axis as a critical regulator of WRN dependency and provide mechanistic insights into resistance to WRN-targeted therapy. Significance: SMARCAL1 and the MRN-ATM pathway determine sensitivity to WRN inhibition in microsatellite instability-high colorectal cancer, revealing key mechanisms of WRN dependency and potential drivers of resistance to WRN inhibitors. (©2026 The Authors; Published by the American Association for Cancer Research.) |
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| Grant Information: | CA274234 National Cancer Institute (NCI); CA275712 National Cancer Institute (NCI); CA278758 National Cancer Institute (NCI) |
| Substance Nomenclature: | EC 3.6.4.12 (Werner Syndrome Helicase) EC 2.7.7.- (SMARCAL1 protein, human) EC 3.6.4.12 (WRN protein, human) EC 3.6.4.- (DNA Helicases) EC 3.1.- (MRE11 Homologue Protein) 0 (Cell Cycle Proteins) 0 (MRE11 protein, human) 0 (DNA-Binding Proteins) 0 (Nuclear Proteins) EC 3.6.- (RAD50 protein, human) EC 6.5.1.- (DNA Repair Enzymes) 0 (NBN protein, human) EC 3.6.- (Acid Anhydride Hydrolases) |
| Entry Date(s): | Date Created: 20260722 Date Completed: 20261015 Latest Revision: 20261017 |
| Update Code: | 20261017 |
| PubMed Central ID: | PMC13669725 |
| DOI: | 10.1158/0008-5472.CAN-26-1023 |
| PMID: | 42484294 |
| Βάση Δεδομένων: | MEDLINE |
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