Wrn-flox Mouse

WRN, encoding the Werner Syndrome RecQ helicase, is a crucial gene involved in genome maintenance. It has roles in processes such as DNA replication, base excision repair, recombination, DNA damage response, and transcription [4,6]. WRN protein is not only a helicase but also an exonuclease and ATPase, playing a key role in maintaining genome stability, especially during DNA replication and telomere metabolism [4].

Cancer cells with microsatellite instability (MSI) are selectively dependent on WRN helicase for survival [1,2,3,5,7]. Inhibition of WRN traps the helicase on chromatin, leading to its degradation via the PIAS4-RNF4-p97/VCP axis in an MSI-H dependent manner [1]. WRN can also unfold cruciform DNA structures formed by TA nucleotide repeats in MSI cells, and together with DNA mismatch repair complexes, it helps prevent DNA breaks and cell lethality [3].

In conclusion, WRN is essential for genome stability and its functions are closely related to DNA-associated processes. The discovery of its synthetic lethal interaction with MSI cancers provides a promising target for cancer therapy. Studies on WRN, especially those exploring its inhibition, may offer new strategies for treating MSI-positive tumors [1,2,3,5,7].