WRN, the gene encoding the Werner Syndrome RecQ helicase, is crucial for genome stability, involved in processes like DNA replication, base excision repair, recombination, DNA damage response, and transcription [4,6,8]. It is also an exonuclease and ATPase, playing a key role particularly during DNA replication and telomere metabolism [6]. Mutations in WRN cause Werner syndrome, a segmental progeroid syndrome with features of premature aging [4,6].

Cancer cells with microsatellite instability (MSI) are dependent on WRN helicase for survival [2,3,5,7,9]. In MSI-H cells, WRN inhibition traps the helicase on chromatin, leading to its degradation via the PIAS4-RNF4-p97/VCP axis [2]. WRN helicase can unfold cruciform DNA structures formed by TA nucleotide repeats, and its downregulation in MSI cells with expanded TA repeats causes DNA breaks and cell lethality [5]. Targeting WRN with small-molecule inhibitors, RNA interference, or EGS/RNase P targeting systems could be beneficial for selective cancer therapy as helicase depletion reduces cell viability due to mitotic catastrophe triggered by replication stress [8]. However, discovering specific non-covalent WRN helicase inhibitors has been challenging due to a high propensity for artefacts via protein interference [1].

In summary, WRN is essential for genome stability, and its role in DNA-related processes is well-established. The discovery of its synthetic lethality in MSI cancers offers a promising target for cancer therapy. The study of WRN in MSI-related cancers through various research models, though facing challenges in inhibitor discovery, may lead to new therapeutic modalities.

References:

1. Heuser, Alisa, Abdul Rahman, Wassim, Bechter, Elisabeth, Möbitz, Henrik, Hamon, Jacques. 2024. Challenges for the Discovery of Non-Covalent WRN Helicase Inhibitors. In ChemMedChem, 19, e202300613. doi:10.1002/cmdc.202300613. https://pubmed.ncbi.nlm.nih.gov/38334957/

2. Rodríguez Pérez, Fernando, Natwick, Dean, Schiff, Lauren, Bashore, Charlene, Basham, Stephen. 2024. WRN inhibition leads to its chromatin-associated degradation via the PIAS4-RNF4-p97/VCP axis. In Nature communications, 15, 6059. doi:10.1038/s41467-024-50178-3. https://pubmed.ncbi.nlm.nih.gov/39025847/

3. Wainberg, Zev A. . WRN Helicase: Is There More to MSI-H than Immunotherapy? In Cancer discovery, 14, 1369-1371. doi:10.1158/2159-8290.CD-24-0771. https://pubmed.ncbi.nlm.nih.gov/39091203/

4. Hisama, Fuki M, Bohr, Vilhelm A, Oshima, Junko. 2006. WRN's tenth anniversary. In Science of aging knowledge environment : SAGE KE, 2006, pe18. doi:. https://pubmed.ncbi.nlm.nih.gov/16807482/

5. Mengoli, Valentina, Ceppi, Ilaria, Sanchez, Aurore, Pettazzoni, Piergiorgio, Cejka, Petr. 2022. WRN helicase and mismatch repair complexes independently and synergistically disrupt cruciform DNA structures. In The EMBO journal, 42, e111998. doi:10.15252/embj.2022111998. https://pubmed.ncbi.nlm.nih.gov/36541070/

6. Katsuya, Tomohiro, Morishita, Ryuichi. . [WRN gene]. In Nihon rinsho. Japanese journal of clinical medicine, 67, 1277-82. doi:. https://pubmed.ncbi.nlm.nih.gov/19591272/

7. van Wietmarschen, Niek, Nathan, William J, Nussenzweig, André. 2021. The WRN helicase: resolving a new target in microsatellite unstable cancers. In Current opinion in genetics & development, 71, 34-38. doi:10.1016/j.gde.2021.06.014. https://pubmed.ncbi.nlm.nih.gov/34284257/

8. Orlovetskie, Natalie, Serruya, Raphael, Abboud-Jarrous, Ghada, Jarrous, Nayef. 2016. Targeted inhibition of WRN helicase, replication stress and cancer. In Biochimica et biophysica acta. Reviews on cancer, 1867, 42-48. doi:10.1016/j.bbcan.2016.11.004. https://pubmed.ncbi.nlm.nih.gov/27902925/

9. Morales-Juarez, David A, Jackson, Stephen P. 2022. Clinical prospects of WRN inhibition as a treatment for MSI tumours. In NPJ precision oncology, 6, 85. doi:10.1038/s41698-022-00319-y. https://pubmed.ncbi.nlm.nih.gov/36379964/