SCF ubiquitin E3 ligase regulates DNA double-strand breaks in early meiotic recombination

Abstract

Homeostasis of meiotic DNA double strand breaks (DSB) is critical for germline genome integrity and homologous recombination. Here we demonstrate an essential role for SKP1, a constitutive subunit of the SCF (SKP1-Cullin-F-box) ubiquitin E3 ligase, in early meiotic processes. SKP1 restrains accumulation of HORMAD1 and the pre-DSB complex (IHO1-REC114-MEI4) on the chromosome axis in meiotic germ cells. Loss of SKP1 prior to meiosis leads to aberrant localization of DSB repair proteins and a failure in synapsis initiation in meiosis of both males and females. Furthermore, SKP1 is crucial for sister chromatid cohesion during the pre-meiotic S-phase. Mechanistically, FBXO47, a meiosis-specific F-box protein, interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells. Our results support a model wherein the SCF ubiquitin E3 ligase prevents hyperactive DSB formation through proteasome-mediated degradation of HORMAD1 and subsequent modulation of the pre-DSB complex during meiosis.

Mlig-SKP1 Gene Is Required for Spermatogenesis in the Flatworm Macrostomum lignano

“…After the knockdown of Mlig-SKP1 by RNAi we observed a phenotype associated with dysfunction of the spermatogenesis process and formation of aberrant sperm, which caused the enlargement of testes and decreased fertility. Recently, a crucial role of SKP1 in mammalian spermatogenesis was demonstrated [ 18 , 20 , 21 ], and here, by showing that SKP1 is required for spermatogenesis in flatworms, we demonstrate that this is an ancient conserved function of this gene.…”

“…According to previous studies of SKP1 , the main role of the SKP1 protein in mammals is being a part of a complex responsible for ubiquitination [ 17 , 18 ]. Importantly, SKP1 was also recently demonstrated to play roles in early meiotic processes in mammals [ 21 ], and in spermatogenesis in particular [ 20 ], by regulating DNA double-stranded break pathways. Hence, our demonstration that in a flatworm SKP1 is also required for spermatogenesis indicates that this is a deeply conserved function of this gene.…”

“…In a nematode, Caenorhabditis elegans , it was shown that SKP1 -related genes perform critical functions in regulating cell proliferation, meiosis, and morphogenesis [ 19 ]. In mammals, SKP1 is involved in the regulation of double-stranded DNA breaks and spermatogenesis [ 20 , 21 ]. In a planarian, Schmidtea mediterranea , knockdown of the SKP1 gene leads to regenerative defects, such as the impaired formation of blastema and the brain [ 22 ].…”

Identification and validation of a 17-gene signature to improve the survival prediction of gliomas

“…S-phase kinase-associated protein 1 (SKP1) is a component of the SCF (SKP1/cullin-1/F-box) ubiquitin ligase complex. SCF complexes play important roles in cell division and cancer progression by degrading specific protein substrates through ubiquitination ( 31 , 32 ). In colorectal cancer, SKP1 is highly expressed and is associated with poor patient prognosis ( 33 ).…”

Chromosome architecture and homologous recombination in meiosis

“…Indeed, SUMO is enriched on chromosome axes and SCs in budding yeast, Sordaria, mice, and humans, and ubiquitin and proteasome have been localized to chromosome axes in budding yeast, C. elegans, and mice (Voelkel-Meiman et al, 2013;Klug et al, 2013;Brown et al, 2008;De Muyt et al, 2014;Ahuja et al, 2017;Rao et al, 2017; Figure 4). Numerous meiotic factors, including cohesin and recombination proteins, undergo SUMOylation in budding yeast (Bhagwat et al, 2021), and the SCF ubiquitin ligase, which regulates SC elongation in conjunction to Pch2 TRIP13 in budding yeast (Zhu et al, 2021), localizes to synapsed chromosome axes and targets HORMAD1 in mouse (Guan et al, 2020;Guan et al, 2022). Future analysis will further elucidate molecular roles of SUMO and the ubiquitin-proteasome system in the regulation of meiotic recombination in conjunction with chromosome architecture.…”