Regulation of FUS ubiquitination and localization by HFM1 is essential for oocyte meiosis prophase I progression in mice

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Abstract
Helicase for meiosis 1 (HFM1), a putative DNA helicase expressed in germ-line cells, has been reported to be closely associated with premature ovarian insufficiency (POI). However, the underlying molecular mechanism has not been elucidated. The aim of this study was to investigate the function of HFM1 in the first meiotic prophase of mouse oocytes. In our study, we found that the deficiency of HFM1 resulted in increased apoptosis and depletion of oocytes in mice. Interestingly, the oocytes were arrested in the first meiotic prophase in the pachytene stage. In addition, impaired DNA double-strand break repair and impaired synapsis were observed in the absence of HFM1. Further investigation revealed that knockout of HFM1 promoted ubiquitination and degradation of FUS protein mediated by FBXW11. Additionally, the depletion of HFM1 altered the intranuclear localization of FUS and regulated meiotic- and oocyte development-related genes in oocytes by regulating the expression of BRCA1. These findings uncovered the critical role of HFM1 in orchestrating the regulation of DNA double-strand break repair and synapsis to ensure meiosis procession and primordial follicle formation, which provided clues for pathogenesis of POI.

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