Can WRN Helicase Inhibitors Treat MSI-H Cancers?
Over 100 years ago, Otto Werner first characterized a recessive autosomal disorder that caused premature, but largely typical, aging in adults, starting by the 3rd decade and resulting in death by the 6th decade via myocardial infarction or cancer. This disease, now known as Werner syndrome, is caused by specific alterations in the 162 KDa Werner syndrome helicase (WRN) protein. WRN is one of the 5 evolutionarily conserved RecQ helicases found in humans. All human RecQ helicases hydrolyze ATP, unwind double stranded DNA, and are proficient at repairing DNA breaks. WRN alone possesses an exonuclease function. While biochemically similar, each of the 5 RecQ helicases has different substrate preferences and differing sets of protein partners. Deficiency or dysfunction in one of these helicases, therefore, presents separate and distinct phenotypes from the others.1
WRN Structure and Function
WRN consists of an N-terminal exonuclease domain, a helicase domain (consisting of an ATPase and a DNA binding RecQ C-terminal domain), a protein interacting HRDC (helicase-and-ribonuclease D C-terminal) domain, and a nuclear localization signal at the C-terminus. The WRN exonuclease functions in a 3’ to 5’ direction. WRN helicase is capable of unwinding DNA duplexes, possessing at least 10 nucleotides of either a 3’ or 5’ single stranded DNA overhang, and is necessary for localizing to the site of telomere damage. The HRDC domain binds DNA and is important for recruiting WRN to double stranded DNA breaks. The region between the RecQ and HRDC domains endows WRN with the ability to anneal single stranded DNA. Mutations in the C-terminal nuclear signal result in misdirection of WRN to the nucleolus, instead of the nucleus. Almost all the genetic alterations that cause Werner syndrome occur in this region.2
The helicase and exonuclease domains can act alone or in concert to address a variety of DNA substrates, such as double stranded DNA breaks, DNA duplexes, replication forks, Holliday junctions, and G-quadruplexes. WRN can act to stabilize replication forks and effect double stranded DNA break repair via classical non-homologous repair joining, homologous recombination repair, or alternate non-homologous repair joining. WRN associates with elements of the shelterin complex to ensure telomere integrity and acts with PARylated TRF1 to repair oxidative damage to telomeres. In the realms of age-related transcriptional regulation and autophagy, WRN is necessary for transcribing nicotinamide nucleotide adenylyl transferase I and producing cellular NAD+. WRN also induces the production of critical autophagic proteins, such as BECLIN-1, ATG5, and LC3II, that initiate autophagy and impair aging.2
WRN Inhibition as a Therapeutic Target
Deficient or impaired production of WRN, whether through nonsense/missense mutation or promoter methylation, produces accelerated senescence and a greatly increased risk of cancer. Cells from Werner syndrome patients contain abnormally high levels of chromosomal deletions, insertions, rearrangements, and mutations. Neoplasms that result are predominantly thyroid cancer, melanoma, meningioma, soft tissue sarcomas, leukemia, and osteosarcoma.3
Even though impaired WRN is at the root of oncogenic genomic instability, cancers that lack adequate mismatch repair machinery and enhanced mutation at microsatellite repeats (MSI-H) depend upon active WRN for their survival. Indeed, the helicase function of WRN seems to enable this subset of colorectal, endometrial, and gastric cancers to persist, in spite of their diminished DNA repair ability. The search for effective WRN inhibitors now offers hope to those who suffer from these MSI-H cancers.4
References
1. Lu, H. and Davis, A. J. (2021) Human RecQ Helicases in DNA Double-Strand Break Repair. Front. Cell Dev. Biol., 25. Review. https://doi.org/10.3389/fcell.2021.640755
2. Gupta, P. et al. (2022) Enigmatic role of WRN-RECQL helicase in DNA repair and its implications in cancer. J Transl Genet Genom 2022;6:147-56. Review. http://dx.doi.org/10.20517/jtgg.2021.60
3. Li, P. et al. (2015) Methylation of Werner syndrome protein is associated with the occurrence and development of invasive meningioma via the regulation of Myc and p53 expression. Experimental and Therapeutic Medicine, 10:498-502. https://doi.org/10.3892/etm.2015.2519
4. Newman, J. A. et al. (2021) Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers. Life Sci. Alliance. 4(1): e202000795. http://doi.org/10.26508/lsa.202000795
