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The role of ubiquitin-conjugating enzyme in the process of spermatogenesis

Reproductive Biology and Endocrinology volume 22, Article number: 110 (2024) Cite this article

Abstract

The ubiquitination is crucial for controlling cellular homeostasis and protein modification, in which ubiquitin-conjugating enzyme (E2) acts as the central player in the ubiquitination system. Ubiquitin-conjugating enzymes, which have special domains that catalyse substrates, have sequence discrepancies and modulate various pathophysiological processes in different cells of multiple organisms. E2s take part in the mitosis of primordial germ cells, meiosis of spermatocytes and the formation of mature haploid spermatids to maintain normal male fertility. In this review, we summarize the various types of E2s and their functions during distinct stages of spermatogenesis.

Introduction

Spermatogenesis, including the mitosis of spermatogonia to self-generation, meiosis and spermiogenesis, involves multiple genes that regulate male haploid gamete formation [1, 2]. The first cells of the reproductive lineage are called primordial germ cells, which can be considered to form the first distinctive subset of embryonic cells in XY embryo, the precursors of spermatogonial stem cells. Primordial germ cells need to be transferred over a considerable distance to facilitate the development of bipotential gonad. Primordial germ cells gradually transform into prospermatogonia as cell expansions [3]. Premeiotic type A single spermatogonia ultimately generate type B spermatogonia via the mitosis of undifferentiated spermatogonia and the process of differentiation into differentiating spermatogonia after birth [4]. Meiotic phase I can br divided into the leptotene, zygotene, pachytene, diplotene and diakinesis stages, in which primary spermatocytes undergo synapsis, DNA double strand breaks, recombination and crossover. Secondary spermatocytes generate two haploid round spermatids with sister chromatid separation [5, 6]. After the maturation and release of spermatids following the 16 steps of spermiogenesis, the lumens of the seminiferous tubules and epididymis are filled with a large amount of haploid sperm [7] (Fig. 1). Unlike those in mammals, the spermatogonia of male fruit flies generate 16 primary spermatocytes, which then synchronously produce 64 round spermatids via meiosis within syncytial cysts. As the round spermatids elongate, the chromatin gradually condenses, and the nucleus transforms from round to dense and needle-like to produce giant mature sperm. The nucleus of the spermatids is located at the end of the cyst, and the tail is located at the other end [8, 9] (Fig. 2). This highly ordered process is regulated by many procedurally generated active proteins [10].

Fig. 1
figure 1

The process of mouse spermatogenesis. Primordial germ cells ultimately generates type B spermatogonia through several rounds of mitosis process. The meiotic phase I can divide into leptotene, zygotene, pachytene, diplotene according on the formation procedure of synaptonemal complex. Homologous chromosomes of primary spermatocytes undergo DNA double strand breaks, synapsis, recombination and crossover (red line and bule line present homologous chromosomes, yellow columns present synaptonemal complex). Secondary spermatocyte generates two haploid round spermatids following with sister chromatids separation. After the process of spermiogenesis, mature sperm are produced to fertilize eggs. Moreover, we add the double-arrow to represent the functional stage of genes Ube2t, Ube2i, Ube2b, Ubc7, Ube2j1 in spermatogenesis

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Fig. 2
figure 2

The process of mouse spermatogenesis. Germ stem cell generates a spermatogonia and a new germ stem cell to maintain the stemness via mitosis. Likewise, cyst stem cell generates a cyst cell and a new cyst stem cell to maintain the stemness. Every two cyst cells encapsulate one spermatogonia. Spermatogonia produces 16 spermatocytes via mitosis. Then, spermatocytes produce 64 round spermatids via meiosis within syncytial cysts, which requiring the involvement of courtless protein. After spermiogenesis, the nucleus of the spermatids is located at the end of the cyst, and the tail is located at the other end

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The ubiquitination-proteasome system is a major mechanism through which proteins are efficiently removed in mammals [10, 11]. Ubiquitination modifications involving ubiquitin (Ub) were first discovered to target nonfunctional or misfolded proteins for degradation [12]. Recently, studies have revealed that ubiquitination not only plays crucial roles in maintaining cell biological function via degradation, but also mediates the activity of multiple proteins via posttranslational modification [13,14,15]. Ubiquitination occurs via three-step enzyme cascades involving ubiquitin activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin ligase (E3), but this process can be reversed by deubiquitinase (DUB). E1 activates ubiquitin in a manner dependent on hydrolysing adenosine 5′-triphosphate (ATP), allowing the ubiquitin molecule to covalently conjugate with E1 to form a thioester-linked complex. The E1-Ub complex then reacts with an E2 enzyme to deliver Ub to E2 via a transthiolation reaction. Finally, an E3 ligase, which can simultaneously bind its target substrate and E2-Ub, transfers the Ub tag to target protein. This process can be arrested to release the monoubiquitinated protein for a particular purpose or can continue multiple times to covalently link a series of additional ubiquitins in a chain for polyubiquitination [16,17,18,19] (Fig. 3). Specifically, small ubiquitin-like modifier proteins are coupled to substrate proteins via a reaction of the dimeric E1 SUMO activators (Sae1/Sae2), E2 (E2 ubiquitin-conjugating enzyme I, Ube2i), and a set of E3 ligases, whereas deSUMOylation is regulated by the Sentrin or SUMO-specific proteases. The process of SUMOylation is similar to that of ubiquitination, both of which play important roles in protein posttranslational modification and are widely involved in the regulation of biological functions, including controlling germ cell development and maturation [20, 21] (Fig. 3). Many studies have reported that altered expression of ubiquitin-conjugating enzymes influences the process of spermatogenesis.

Fig. 3
figure 3

The cycle of ubiquitination and SUMOylation. A Activation: E1 activates ubiquitin with ATP. Conjugation: E2 reacts with E1-Ub complex to deliver Ub to E2. Ligation: E3 simultaneously bind its target substrate and E2-Ub to transfer one or more Ub for substrate. Deubiquitination: ubiquitin can be removed through deubiquitinase. B Activation: Sae1/Sae2 is activated with ATP to bind SUMO. Conjugation: Ubc9 interacts with E1-SUMO complex to transfer SUMO to Ubc9. Ligation: E3 simultaneously reacts with its target substrate and Ubc9-SUMO to send SUMO to substrate. DeSUMOylation: SUMO can be eliminated via Sentrin or SUMO-specific proteases. E1: ubiquitin activating enzyme. E2: ubiquitin-conjugating enzyme. E3: ubiquitin ligase. DUB: deubiquitinase

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Genes in the E2 protein family have significant sequence discrepancies that result in a diversity of ubiquitin-conjugating enzymes in various species, but all of them contain a specific domain called the ubiquitin-coupled catalytic (UBC) domain, which consists of 150 to 200 amino acids [22,23,24]. UBC also contains a typical topological structure, as well as a motif including histidine-proline-asparagine tripeptides and catalytic cysteine residues [25]. Recently, whole-genome sequencing analysis of the sperm whale revealed 39 UBE2 genes, which may contribute to functional divergence [26]. Similarly, humans harbour forty E2 genes, including intact genes, partial genes and pseudogenes [27]. Given the pivotal role in transmission of ubiquitin and the critical role of ubiquitin-conjugating enzymes in regulation of the activity of downstream proteins, we provide a comprehensive overview on the roles of ubiquitin-conjugating enzymes in spermatogenesis (Fig. 1) and review their corresponding E3 partners in Table 1.

Table 1 The role of ubiquitin-conjugating enzyme in spermatogenesis and their corresponding E3 ligases
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Ubiquitin-conjugating enzyme in primordial germ cells

Spermatogenesis is initiated by triggering spermatogonial stem cells to undergo mitotic division to generate progenitors during the migration phase, which further produces differentiated types of spermatogonia [65].

E2 ubiquitin-conjugating enzyme T (UBE2T), a crucial component of the FA pathway that serves as an indispensable way to maintain reproductive capacity, collaborates with FANCL to regulate ubiquitination [66, 67]. Ube2t deficient mice exhibit severe loss of primordial germ cells at 3 days of age and smaller ovaries or testes without differences in body weight. Knockout of Ube2t results in normal primordial germ cells migration but defective expansion with increased DNA damage, which triggers p53 pathway activation to slow the cell cycle. Moreover, Ube2t can offset transcription–replication conflicts, which are the source of replication stress by resolving R-loops, protecting replication forks and maintaining the stability of common fragile sites to maintain genomic stability in primordial germ cells. UBE2T promotes the rapid proliferation of mouse primordial germ cells to ensure the establishment of fertility [68].

Ubiquitin-conjugating enzyme in meiosis

The halved genetic reduction in a particular cell division is known as meiosis, accompanied by two successive rounds of chromosome separation after a single round of DNA replication. Homologous chromosomes separate into opposite poles at meiosis I, and then sister chromatids separate into opposite poles at meiosis II [69]. During early meiosis I, programmed DNA double strand breaks are associated with dynamic changes in chromosomal structure, and chromatin remodelling is modulated mainly by histones. Histones are involved in the resumption of meiosis, meiotic sex chromosome inactivation and asymmetric division [70,71,72]. Following the development of spermatocytes, the synaptonemal complex gradually forms with the assembly of lateral elements, axial elements, central elements and transverse filaments between homologous chromosomes. The synaptonemal complex maintains synapsis along the full length of each synaptonemal chromosome, sustains crossover, and promotes the exchange of DNA strands [73, 74]. Synaptonemal complex is vital for the successful progression of meiosis.

UBC7, which is located on the plasma and ER membranes along with calreticulin, participates in phagocytosis and self-polyubiquitinates on the cystine residues to yield its degradation [75,76,77]. The Courtless (col) gene, encoding the Drosophila homologue of yeast UBC7, maps to polytene chromosome band 47D. Col mutation in Drosophila is caused by the insertion of a P element into the 3’-UTR, which probably disrupts translational regulatory elements. Homozygous mutants led to the accumulation of courtless protein and aberrant courtship in male flies. Only 5% of the homozygous mutants finished courtship, and their matings gave no progeny. Homozygous mutants undergo normal mitotic divisions of primary spermatogonial cells to produce 16 primary spermatocytes but do not undergo meiotic divisions to generate normal haploid spermatids [78](Fig. 2). In addition, human UBE2G2, which was isolated from a human foetal-brain cDNA library, is a Ubc7 homologue [79]. Two studies including subfertile males estimated the correlation between alterations in sperm DNA methylation levels and semen parameters via deep bisulfite sequencing. Then, they discoverd abnormal methylation levels at CpG sites in UBE2G2 gene amplicons in the oligospermic group [80, 81]. This abnormal change may indicate that UBE2G2 plays a key role during human spermatogenesis, but more rigorous and scientific evidence is lacking.

The centre of the sumoylation cascade is a single E2 SUMO-conjugating enzyme, UBE2I, which is also known as UBC9 and is required for sumoylation [82]. In the testes of Chinese mitten crabs, Ube2i expression is low during early development, reaches its highest level during rapid testes growth (Stage II), and then gradually decreases to low levels [83]. In yeast, the Ubc9-K153R/157R sumoylation deficient mutant is dispensable for growth under vegetative and stress conditions. Ubc9 sumoylation, which governs meiotic SUMO conjugates, SUMO chains, and synaptonemal complex associated genes, is a key regulatory factor in synaptonemal complex formation. Experimental results revealed that defects in the ubc9-K153/157R mutant generated on the downstream of synapsis, such as the formation of DNA double strand breaks, homology search, and the formation of synapsis initiation complexes, although the mutant was defective in producing even short stretches of synapsis [84]. Similarly, Ube2i was discovered to be expressed in pachytene spermatocytes and localized to synaptic complexes in mice [85]. Another study unveiled that in mouse spermatocytes, Ube2i was located at synaptonemal complexes, the XY body in pachytene and diplotene, and centromeres in metaphase I by immunofluorescence staining [86]. Global Ube2i knockout mice are embryonic lethal at embryonic day 7.5 because of the mitotic defects caused by abnormal chromatin condensation, chromosome segregation and nuclear reorganization [82]. Although conditional Ube2i knockout in female mouse proved that the loss of Ube2i in oocytes caused the arrest of folliculogenesis and abnormal communication with ovarian somatic cells, the function of Ube2i in the spermatogenesis of mammals is still unknown [87].

Yeast RAD6, which functions as an E2 ubiquitin-conjugating enzyme, mainly regulates DNA postreplication repair and protein degradation through the N-end rule pathway [88,89,90]. RAD6 mediates the ubiquitination of histone 2B (H2B) at Lys 123 and then promotes the methylation of histone 3 (H3) at lysine 4 in yeast [91]. RAD6 is essential for sporulation and regulates the structure of chromatin via histone ubiquitination [92]. Unlike yeast, the mammalian RAD6 homologue is encoded by RAD6A and RAD6B (also called UBE2B). UBE2B is expressed in many cells but is especially highly expressed in spermatocytes and round spermatids [93, 94]. Although testicular tissue sections from Ube2b knockout mice exhibit abnormalities predominantly during spermiogenesis (we describe this phenomenon later in terms of ubiquitin-conjugating enzyme in spermiogenesis), a TUNEL assay revealed massive numbers of apoptotic spermatocytes in the seminiferous tubules of Ube2b knockout mice. The results of meiotic chromosome spread assay, which was performed with spermatocytes from Ube2b knockout mice, revealed that the average total width of the synaptonemal complex was thinner, and the average total length of the synaptonemal complex was significantly increased in late pachytene, and the loss of telomeres occurred during pachytene. Moreover, the number of chiasmata in spermatocytes from Ube2b knockout mice was increased in middle pachytene. All of these findings may be attributed to premature synaptonemal complex degradation in spermatocytes in Ube2b knockout mice [95, 96].

Homologous chromosome pairing commences at the zygotene stage and is complete at the pachytene stage, but mammalian heterologous X and Y chromosome pairing occurs only in the pseudoautosomal region. Unsynapsed X and Y chromosome arms trigger XY body formation and meiotic sex chromosome inactivation during the transition from zygotene to pachytene [97, 98]. Interestingly, histone H2AK119ub1 was enriched on the XY body with accumulation of the RAD6B enzyme [95, 99]. Additionally, H2BT119 phosphorylation, which is markedly elevated and distributed along the unpaired axial elements of sex chromosomes in pachytene and diplotene spermatocytes, extends to the XY body at gradually lower levels. However, immunofluorescence staining showed no difference in the degree of histone H2AK119 and H2BK120 ubiquitination or H2BT119 phosphorylation between the control group and the Ube2b knockout group. H2AT120 phosphorylation was found to be high in leptotene and zygotene spermatocytes but was lost in early pachytene spermatocytes, with the exception of the XY body. In Ube2b knockout spermatocytes, H2AT120 phosphorylation was strikingly increased during pachytene and diplotene, with increased signals on the XY body. However, H2AXS139 phosphorylation did not differ between in wild-type and Ube2b knockout spermatocytes. In addition, H3K4 methylation also strongly increased in nuclei and XY body in diplotene and extended to the metaphase II phase in Ube2b knockout spermatocytes. In contrast, the levels of H3K9m2, which represents silent chromatin, were much lower on centromeric heterochromatin but normal on sex chromatin in Ube2b-deficient germ cells [100, 101].

Ubiquitin-conjugating enzyme in spermiogenesis

During spermiogenesis, round spermatids undergo giant structural alterations, including the formation of sperm acrosomes involving the Golgi apparatus, the dynamics of nuclear chromatin, the formation of the sperm flagellum, the rearrangement of mitochondria at the tail of the sperm, and the removal of redundant cytoplasm [102, 103] (Fig. 4).

Fig. 4
figure 4

The main process of spermiogenesis with the transformations of histones to protamine. Round spermatids undergo 16 steps to generate normal elongated sperm. Golgi apparatus gradually form sperm acrosome. Sperm flagellum gradually is elongated with microtubule proteins and rearrangement of mitochondria. Redundant cytoplasm was removed at last, and Ube2j1 plays an indispensable role in this process. We only show 5 stages of spermatids to present this procedure following the transformations of histones to protamine, for which Ube2b is crucial

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The proteasomal degradation pathways strongly participate in spermiogenesis accompanied by unnecessary protein extraction form the endoplasmic reticulum to the cytosol [104]. UBE2J1 is located on the membrane of the endoplasmic reticulum and has tail-anchored protein domains [105, 106]. The SEL1L dislocation complex, which contains several factors, including UBE2J1, is known to be involved in ER dislocation [107]. A study revealed that Ube2j1 was strongly expressed in the maturation phase of elongated spermatids between steps 12 and 15, a period in which the ER undergoes massive and dynamic changes. Global Ube2j1 knockout mice were generated from heterozygous mice, and only half of all the mice survived at postnatal day 21. The survivors of the Ube2j1 knockout mice were smaller in body size and were significantly lighter in weight than the wild-type mice, but the average weight of testes was normal. Moreover, Ube2j1 knockout female mice were fertile, but male mice were sterile with severe defects in sperm morphology and mobility. The sperm of Ube2j1 knockout mice presented with excess residual cytoplasm around the acrosome, neck and midpiece of the flagellum (Fig. 4). The failure of cytoplasmic removal of Ube2j1 gene knockout in mice ultimately leads to male infertility [108]. Rnf133, a RING family E3 ubiquitin ligase, was tested for its ability to interact with Ube2j1. Knocking out Rnf133 in male mice leads to a severe subfertility with aberrant head–neck morphology. Similar abnormalities were previously shown in Ube2j1 KO sperm [109].

A previous study revealed that Ube2b knockout in mice resulted in smaller testes and male infertility. Hematoxylin-eosin staining reveled that the development of germ cells may arrest between spermatogenic stages I–IV and V–VIII [96]. Another study confirmed that Ube2b deficiency was indispensable for meiosis but resulted in failure of spermiogenesis with abnormal spermatozoa. Occasionally, a nearly complete lack of all germ cell types was detected in 10-20% of the male Ube2b knockout mice. Multiple hookless heads, including club-shaped heads, amorphous heads, and those with disintegrated nuclei or no nuclei, were observed in Ube2b knockout testes [110]. Ube2b promoted the ubiquitination of histones 2 A and 2B, and its deficiency influenced histone-to-protamine replacement during sperm head formation [103, 111] (Fig. 4). Testes-specific histone H2B, a representative marker of the elongation phase but lacking in mature spermatids, was irregularly displayed on abnormal spermatids and detected in the epididymis ducts, suggesting that round or elongating spermatids were prematurely released [111]. The genes, whose expression was repressed in normal spermatids, were increased in Ube2b-deficient cells, which may indicate that X chromosomal gene silencing was impaired in Ube2b knockout spermatids [101]. This may be related to the failure of spermiogenesis.

In humans, a study in India analysed genetic variations in the UBE2B gene in 530 infertile males (including 350 with azoospermia, 105 with oligoasthenoteratozoospermia, and 75 with oligoasthenozoospermia) and 300 control males. Sequence analysis revealed 5 single-nucleotide substitution polymorphisms in 37.5% of infertile males and 7.3% of fertile males, two (g.5197:T > G; g.9157:A > G) of which were novel and found only in infertile males [112]. Moreover, an analysis was carried out to investigate single nucleotide polymorphism differences in UBE2B in 312 fertile males and 388 infertile males in Northeast China. The UBE2B polymorphisms g.-293T > G, g.20016A > G and g.9157A > G were not associated with male infertility [113]. Another analysis of 776 idiopathic azoospermia patients and 709 fertile men revealed two novel synonymous variants in the exon region and four novel variants in the promoter region of UBE2B in the Chinese population, among which one variant (Chr5.133706925 A > G) was highly prone to idiopathic azoospermia and inhibited the transcriptional regulation activity of specificity protein 1 [114]. Single and dual CGG deletions in the 5’-UTR of the UBE2B gene increased the binding of the transcription factor specificity protein 1 to the promoter, which may be related to human male infertility [115]. Another study from the USA revealed mRNA alterations in the UBE2B gene in 326 oligozoospermic patients and 421 normal men. A total of 4.6% of the oligozoospermic patients were discovered to have nine splicing, four missense and two nonsense alterations in UBE2B mRNA, but these mutations were not found in unaffected men. The sequence of the corresponding DNA regions did not reveal causative DNA mutations, suggesting posttranscriptional defects in spermatogenesis [116]. Combined with the previous description of meiosis, we hypothesize that the UBE2B gene may play a different role at a given point in spermatogenesis.

Ubiquitin-conjugating enzyme makes no impact on the process of spermatogenesis

Various proteins are highly expressed in the progression of spermatogenesis, some of which may play indispensable roles in generating normal sperm. Some genes, such as G3bp2, Tex33, Asb15, are nonessential for mouse spermatogenesis [117,118,119].

UBE2W was identified as a ubiquitin-conjugating enzyme that mediates the N-terminal ubiquitination of substrates [57, 120]. The levels of Ube2w in mouse testes gradually increased with the development of newborn to adult mice. Loss of ube2w lead to susceptibility to early postnatal lethality, abnormalities in skin maturation and severe declines in male fertility accompanied by vacuolation of the seminiferous tubules. Testes of Ube2w KO mice displayed variable degeneration and atrophy of seminiferous tubules, ranging from mild vacuolation to complete vacuolation. In addition, histological staining revealed that sperm levels in the KO epididymis varied, ranging from a normal number of mature spermatozoa to a complete absence of mature spermatozoa. This suggested ube2w-deficient male mice was oligozoospermia, but the process of spermatogenesis was normal. However, ube2w deficiency did not affect the tolerance of germ cells to DNA cross-linking induced by mitomycin C or the cellular response to oxidative and endoplasmic reticulum stress [121]. Moreover, under conditions of RNF4 (a ubiquitin ligase) deficiency, inactivation of Ube2w promoted the response to DNA cross-linking damage [122]. In addition, downregulated expression of Ube2w in a mouse-derived spermatogonia cell line and spermatocyte cell line significantly increased the number of apoptotic cells via the P53/Bcl-2/caspase 6/caspase 9 signalling pathways [123]. Thus, we speculated that the decreased number of sperm in Ube2w knockout male mice due to apoptosis rather impaired spermatogenesis.

UBC4, which is induced by heat stress, is essential for the degradation of short-lived and abnormal peptides but not for long-lived proteins in Saccharomyces cerevisiae [124]. During spermatogenesis, massive amounts of intracellular histones are degraded in a manner dependent on UBC4 as round spermatids transform into elongated mature forms [125, 126]. A pervious study revealed that various UBC4 isoforms activate ubiquitin conjugation and participate in cellular remodelling and protein degradation during postnatal development of the rat testes [127]. However, another study revealed that Ubc4 knockout mice presented normal body weight and fertility. Compared with that of the control mice, the testicular weight of the Ubc4-deficient male mice decreased 10% after the end of the first wave of spermatogenesis, and then reached a normal weight at postnatal day 65. The number and motility of sperm isolated from the epididymides of the Ubc4 knockout mice were normal. Under heat stress, there was no difference in cell apoptosis or testes mass [128].

Conclusions and perspective

Ubiquitin-conjugating enzymes play key regulatory roles in protein degradation and affect signalling pathways, including those involved in DNA damage repair, intracellular trafficking, endocytosis, the regulation of cell membrane fluidity and inflammatory responses [129,130,131]. In this paper, we reviewed and illustrated the various functions of E2 enzymes involved in different stages of spermatogenesis, including expansion of primordial germ cells, spermatocyte meiosis, and sperm metamorphosis. With the exception of the E2 enzymes we summarized above, the functions of other E2 enzymes in spermatogenesis and the substrates of E2s remain unknown. In the future, with the development of biotechnology, the functions of more ubiquitin-conjugating enzymes will be better clarified during spermatogenesis. Moreover, in light of the function of E2s in the ubiquitination system and spermatogenesis, targeting E2s may be a novel strategy for the treatment of azoospermia patients via cell and gene therapy.

Availability of data and materials

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Ub:

Ubiquitin

E1:

Ubiquitin activating enzyme

E2:

Ubiquitin-conjugating enzyme

E3:

Ubiquitin ligase

DUB:

Deubiquitinase

ATP:

Hydrolyzing adenosine 5′-triphosphate

UBC:

Ubiquitin coupled catalytic

UBE2T:

E2 ubiquitin-conjugating enzyme T

UBC7:

E2 ubiquitin-conjugating enzyme 7

Col:

Courtless

UBE2G2:

Ubiquitin-conjugating enzyme E2 G2

UBE2B:

E2 ubiquitin-conjugating enzyme B

RAD6B:

RAD6 homolog B

UBE2I:

E2 ubiquitin-conjugating enzyme I

UBE2W:

E2 ubiquitin-conjugating enzyme W

UBC4:

E2 ubiquitin-conjugating enzyme 4

UBE2J1:

E2 ubiquitin-conjugating enzyme J1

H2B:

Histone 2B

H3:

Histone 3

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Acknowledgements

The authors would like to thank all researchers included in the studies we reviewed.

Funding

This work was supported by the National Natural Science Foundation of China (82072838).

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Authors and Affiliations

  1. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Peng Lv, Jihong Liu & Xiaming Liu

  2. Institute of Andrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Peng Lv, Jihong Liu & Xiaming Liu

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  1. Peng Lv
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  2. Jihong Liu
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Data collection, writing and editing of the manuscript: Peng Lv. Supervision and paper review: Jihong Liu and Xiaming Liu. All authors contributed to the article and approved the submitted version. All authors reviewed the manuscript.

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Lv, P., Liu, J. & Liu, X. The role of ubiquitin-conjugating enzyme in the process of spermatogenesis. Reprod Biol Endocrinol 22, 110 (2024). https://doi.org/10.1186/s12958-024-01282-y

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Keywords

Reproductive Biology and Endocrinology

ISSN: 1477-7827

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