Comment on “Farnesylation-Dependent Kinetochore Targeting of Centromere Protein F Is Essential for Oocyte Meiotic Progression and Female Fertility”

Successful cell division during meiosis is dependent on accurate chromosome segregation; the role of centromeres, kinetochores, and spindle microtubules is well characterized in mitosis, but the role of certain proteins surrounding them remains uncertain in meiosis. This is important to understand because the arrest of maturation of oocytes is a common origin of female infertility, but the mechanisms for this are largely unknown. This study was designed to assess the regulatory mechanism of the farnesylation of centromere protein F on its meiotic function as well as evaluate any association between mutations in centromere protein F and female oocyte maturation disorders. This study used oocyte microinjection, western blotting, co-immunoprecipitation, and immunofluorescence to characterize the role of centromere protein F. During mitosis, this protein assists in chromosome segregation, but it is currently unknown if its role remains the same during meiosis. This study used a mouse model to explore both genetic and pharmacologic methods of farnesylation, and to verify the mechanism of mutations in oocyte maturation. Microinjection of centromere protein F siRNA reduced maturation rates significantly, with many halting maturation at metaphase I ( P <0.05). Farnesylation likewise reduced the rate of oocyte maturation ( P <0.01), and additionally weakened the interationc between centromere protein F and Aurora kinase B, which was confirmed by co-immunoprecipitation ( P <0.01). Farnesylation also disrupted kinetochore localization, contributing to the arrest of oocyte maturation. Immunofluorescence analysis further showed that centromere protein F localized at kinetochores by metaphase I, causing arrested development. Screening human patients with infertility resulted in the identification of 4 individuals with rare heterozygous variants in the CENP-F gene that were associated with the arrest of oocyte maturation. When testing centromere protein F derived from patients who were identified to have a genetic mutation in this protein, microinjection of the patient-derived centromere protein F also caused significantly reduced maturation in mouse oocytes ( P <0.01). Two identified mutations reduced the fanesylation of centromere protein F as well as disrupted kinetochore localization and damaged the Aurora kinase B interaction. These results indicate that there is a direct association between centromere protein F mutations and infertility, specifically the arrest of oocyte maturation during meiosis. These findings contribute evidence to the controversy surrounding the influence of farnesylation on the localization of CENP- F, with some previous studies showing no effect of farneslyation and others showing a direct interaction between molecules that is dependent on farneslyation. This study emphasizes the need for further clinical research to validate the pathology of these mutations in diverse populations. Future studies should also attempt to ethically validate the results of these mouse models in human models and examine other possible mechanisms for arrested maturation of oocytes such as disruption of microtubule binding. (Summarized from Zhong O, Wang C, Zhang J, et al. Farnesylation-dependent kinetochore targeting of centromere protein F is essential for oocyte meiotic progression and female fertility. Am J Obstet Gynecol. 2026;234:116-140. doi: 10.1016/j.ajog.2025.08.031)