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Synaptonemal complex mutants affect Sororin localization. Spermatocytes spreads from animals with the indicated genotypes were immunostained with antibodies as shown. a Spreads prepared from Sycp1−/− spermatocytes were probed with antibodies to both SYCP3 and Sororin. In these samples, no clear staining for Sororin was detected. b Spreads prepared from Sycp3−/− spermatocytes were probed with CREST serum, to identify centromeres and either anti-Sororin or anti-SYCP1 antibodies. Short linear Sororin-positive tracks (white arrowheads) are similar to those seen with anti-SYCP1 antibody from identical preparations. Scale bar = 20 μm
Source publication
During meiotic prophase, cohesin complexes mediate cohesion between sister chromatids and promote pairing and synapsis of homologous chromosomes. Precisely how the activity of cohesin is controlled to promote these events is not fully understood. In metazoans, cohesion establishment between sister chromatids during mitotic divisions is accompanied...
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Citations
... CDCA5, also known as Sororin, is a key regulator for segregating sister chromatids during S and G2/M phases of the cell cycle [5]. CDCA5 protein maintains the cohesion of sister chromatids and ensures accurate chromosome separation during mitosis [6]. Recent studies have highlighted the significant role of CDCA5 in tumorigenesis and tumor progression. ...
Background
Cell division cycle associated 5 (CDCA5) plays ontogenetic role in various human cancers. However, its specific function and regulatory mechanism in ccRCC remain uncertain.
Methods
Immunohistochemistry and western blots were performed to investigate the expression of CDCA5 in ccRCC tissues. Genetic knockdown and upregulation of CDCA5 were performed to investigate its functional roles in ccRCC proliferation, migration, apoptosis and sunitinib resistance. Furthermore, Co-IP assay and LC–MS/MS were performed to investigate the underlying mechanisms.
Results
We found that CDCA5 expression is frequently upregulated in ccRCC tumors and is associated with poor prognosis of ccRCC patients. Functionally, CDCA5 promotes proliferation, migration, and sunitinib resistance, while inhibiting apoptosis in ccRCC cells. In vivo mouse xenograft model confirms that silencing of CDCA5 drastically inhibits the growth of ccRCC. Mechanistically, we discovered that CDCA5 interacts with Eukaryotic Translation Elongation Factor 1 Alpha 1 (EEF1A1) to regulate mTOR signaling pathway, thereby promoting ccRCC progression.
Conclusions
Taken together, our results demonstrate the significant role of CDCA5 in ccRCC progression. The findings may provide insights for the development of new treatment strategies targeting CDCA5 for ccRCC patients.
... Although we do not know the nature of these connections, one possibility is that during centromere-pairing, chromatin loops from the two partners become connected by cohesin, forming a flexible bridge that would explain the interdependent movements of the mini-chromosomes studies here. Indeed, we showed previously in budding yeast that prophase centromere pairing cannot ensure proper segregation in sgo1D mutants, in which cohesin is not protected at meiosis I centromere 32 .Cohesin is enriched at meiotic centromeres and numerous studies suggest that cohesion establishment may be active in meiotic prophase[28][29][30][31] (reviewed in 32 ) making cohesion a plausible candidate for linking partner centromeres.The high fidelity of mini-chromosome segregation following centromere pairing has important implications for natural chromosomes. Although non-exchange partners, like the minichromosomes, have provided a unique way to observe how centromere pairing can influence disjunction, in budding yeast, non-exchange partners occur in only a few percent of ...
Proper chromosome segregation in meiosis I relies on the formation of connections between homologous chromosomes. Crossovers between homologs provide a connection that allows them to attach correctly to the meiosis I spindle. Tension is transmitted across the crossover when the partners attach to microtubules from opposing poles of the spindle. Tension stabilizes microtubule attachments that will pull the partners towards opposite poles at anaphase. Paradoxically, in many organisms, non-crossover partners segregate correctly. The mechanism by which non-crossover partners become bi-oriented on the meiotic spindle is unknown. Both crossover and non-crossover partners pair their centromeres in early in meiosis (prophase). In budding yeast, centromere pairing, is correlated with subsequent correct segregation of the partners. The mechanism by which centromere pairing, in prophase, promotes later correct attachment of the partners to the metaphase spindle is unknown. We used live cell imaging to track the bi-orientation process of non-crossover chromosomes. We find that centromere pairing allows the establishment of connections between the partners that allows their later interdependent attachment to the meiotic spindle using tension-sensing bi-orientation machinery. Because all chromosome pairs experience centromere pairing, our findings suggest that crossover chromosomes also utilize this mechanism to achieve maximal segregation fidelity.
... CDCA5, also known as Sororin, is a key regulator for segregating sister chromatids in S and G2/M phases of the cell cycle [8]. CDCA5 protein could maintain the cohesion of sister chromatids and ensure accurate chromosome separation during mitosis [9]. CDCA5 can also promote cell proliferation and participate in apoptosis by regulating the function of cell cycle related proteins and transcription factors [10]. ...
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer in adult, and patients with advanced ccRCC are facing limited treatment options. Cell division cycle associated 5 (CDCA5), a key regulator for segregating sister chromatids in cell cycle, has been increasingly reported for a potential therapeutic target in multiple human cancers. However, the functional roles of CDCA5 in ccRCC remain uncertain. Here we identified that CDCA5 expression was frequently upregulated in ccRCC tumors and significantly associated with poor prognosis of ccRCC patients. To investigate the role of CDCA5 in ccRCC progression, loss function cell models were established. Knockdown of CDCA5 remarkably suppressed ccRCC cell proliferation and migration ability, and also induced cell apoptosis in vitro. In addition, the significance of CDCA5 in ccRCC was further demonstrated in a mouse xenograft model. Silencing of CDCA5 drastically inhibited in vivo tumorigenicity of ccRCC cells. Mechanically, we identified CDCA5 may cooperate with EEF1A1 to promote the tumorigenic phenotype of ccRCC. Overall, our results revealed the significant functional role of CDCA5 in ccRCC progression, which may pave a way for the development of new treatment strategies for ccRCC treatment.
... cell division cycle-associated 5 (cdca5), also known as sororin, is the encoding gene of cdca5, which is located on chromosome 11. cdca5 is a transcriptional protein with a molecular weight of ~27 kda (8,9) that is widely expressed in bone marrow, testes, lymph nodes, bladder, lung, breast, stomach, and other tissues and organs (10,11). cdca5 has been reported to promote cancer (10,12,13). ...
... cdca5 enhanced the proliferation and inhibited the apoptosis of bladder cancer cells (10,13). cdca5 promoted bladder cancer cell proliferation by activating the akt signaling pathway in bladder tumors (9). in the present study, cdca5 knockdown inhibited breast cancer cell proliferation, and the expression level of proliferation-related proteins was downregulated following cdca5 knockdown. ...
Breast cancer is one of the most common malignant tumors in women. Cell division cycle‑associated 5 (CDCA5) is closely associated with the behavior of various cancer types. The aim of the present study was to explore the effect of CDCA5 on breast cancer. Western blot analysis and reverse transcription‑quantitative PCR were used to detect the expression level of CDCA5 in human normal mammary cells and human breast cancer cell lines. To determine its function in MDA‑MB‑231 cells, CDCA5 was silenced in MDA‑MB‑231 cells by transient short hairpin RNA transfection. Cell Counting Kit‑8 and clonogenicity assays were used to evaluate cell proliferation. Wound healing and Transwell assays were used to detect cell invasion and migration. Western blot analysis was used to detect the protein expressions of Ki67 and PCNA associated with proliferation, MMP2 and MMP9 associated with migration. CDCA5 was found to be markedly increased in breast cancer cell lines. CDCA5 knockdown was able to suppress cell proliferation, invasion and migration. CDCA5 inhibition downregulated PDS5 cohesin‑associated factor A (PDS5A) expression in breast cancer cells. PDS5A overexpression was found to reverse the effect of CDCA5 inhibition on breast cancer cell proliferation and migration. CDCA5 knockdown was shown to suppress the malignant progression of breast cancer cells by regulating PDS5A. The present findings may provide new potential targets for breast cancer therapy.
... Rather surprisingly, the WAPL antagonist Sororin localizes only in the central region of the synaptonemal complex, whereas the other subunits of the cohesin complex do not localize in this region, and its presence on meiotic chromosome axes correlates with the appearance of the central element protein SYCP1. This suggests that in meiosis, Sororin might have different functions from what described in mitosis (Gomez et al., 2016;Jordan et al., 2017). ESCO1 role in meiosis has not been investigated yet, but ESCO2 and acetylated SMC3 are mostly detected upon synapsis formation in zygotene (McNicoll et al., 2020). ...
One of the most fascinating aspects of meiosis is the extensive reorganization of the genome at the prophase of the first meiotic division (prophase I). The first steps of this reorganization are observed with the establishment of an axis structure, that connects sister chromatids, from which emanate arrays of chromatin loops. This axis structure, called the axial element, consists of various proteins, such as cohesins, HORMA-domain proteins, and axial element proteins. In many organisms, axial elements are required to set the stage for efficient sister chromatid cohesion and meiotic recombination, necessary for the recognition of the homologous chromosomes. Here, we review the different actors involved in axial element formation in Saccharomyces cerevisiae and in mouse. We describe the current knowledge of their localization pattern during prophase I, their functional interdependence, their role in sister chromatid cohesion, loop axis formation, homolog pairing before meiotic recombination, and recombination. We also address further challenges that need to be resolved, to fully understand the interplay between the chromosome structure and the different molecular steps that take place in early prophase I, which lead to the successful outcome of meiosis I.
... LE components include meiosis-specific axial proteins (SYCP2 and SYCP3) and cohesin complexes, which collectively form a core between each pair of sister chromatids. The LEs of a pair of homologous chromosomes are bridged together by a series of transverse filaments (SYCP1) and central region proteins (SYCE1-SYCE3, TEX12 and sororin) (Cahoon and Hawley, 2016;Gao and Colaiácovo, 2018;Gómez et al., 2016;Jordan et al., 2017). Synapsis and crossover recombination between homologous chromosomes is completed by the pachytene sub-stage of meiotic prophase (Cole et al., 2012;Gao and Colaiácovo, 2018). ...
Precise control of chromosome dynamics during meiosis is critical for fertility. A gametocyte undergoing meiosis coordinates formation of the synaptonemal complex (SC) to promote efficient homologous chromosome recombination. Subsequent disassembly of the SC occurs prior to segregation of homologous chromosomes during meiosis I. We examined the requirements of the mammalian Aurora kinases (AURKA, AURKB and AURKC) during SC disassembly and chromosome segregation using a combination of chemical inhibition and gene deletion approaches. We find that both mouse and human spermatocytes fail to disassemble SC lateral elements when the kinase activity of AURKB and AURKC are chemically inhibited. Interestingly, both Aurkb conditional knockout and Aurkc knockout mouse spermatocytes successfully progress through meiosis, and the mice are fertile. In contrast, Aurkb , Aurkc double knockout spermatocytes fail to coordinate disassembly of SC lateral elements with chromosome condensation and segregation, resulting in delayed meiotic progression. In addition, deletion of Aurkb and Aurkc leads to an accumulation of metaphase spermatocytes, chromosome missegregation and aberrant cytokinesis. Collectively, our data demonstrate that AURKB and AURKC functionally compensate for one another ensuring successful mammalian spermatogenesis.
This article has an associated First Person interview with the first author of the paper.
... WAPL decorates the AEs/LEs of chromosomes in mouse oocytes (Zhang et al., 2008) and spermatocytes, where it is involved in the removal of arm cohesion by the end of prophase I (Brieño-Enríquez et al., 2016). Unexpectedly, Sororin has been detected at the SC central region, unlike the cohesin subunits and WAPL (Gómez et al., 2016;Jordan et al., 2017). ...
... http://dx.doi.org/10.1101/763797 doi: bioRxiv preprint first posted online Sep. 10, 2019; respectively, as previously reported in wild-type spermatocytes (Brieño-Enríquez et al., 2016;Gómez et al., 2016;Jordan et al., 2017). Centromeric cohesion defects were not evident in deficient Pds5AB zygotene and early pachytene spermatocytes, as kinetochore signals appeared unaltered at the ends of AEs/LEs or SCs, respectively, as in Pds5AB proficient mid pachytene spermatocytes ( Fig. S7M-O). ...
... Likewise, similar distribution patterns have been previously reported in mouse meiosis for the cohesin cofactors WAPL (Zhang et al., 2008;Brieño-Enríquez et al., 2016), andNIPBL andMAU2 (Visnes et al., 2014). The exception is Sororin, which localizes at the central region of the SC (Gómez at al., 2016;Jordan et al., 2017). ...
Cohesin cofactors regulate the loading, maintenance and release of cohesin complexes from chromosomes during the mitotic cell cycle but little is known on their role during vertebrate meiosis. One such cofactor is PDS5, which exists in two versions in somatic and germline cells, PDS5A and PDS5B, with unclear functional specificity. Here we have analyzed their distribution and functions in mouse spermatocytes. We show that simultaneous elimination of PDS5A and PDS5B results in severe defects during prophase I while their individual depletion does not, suggesting a functional redundancy of the two factors. Shortened axial/lateral elements and a reduction of early recombination nodules are observed in the absence of both PDS5 proteins. Moreover, telomere integrity and their association to the nuclear envelope are severely compromised. As these defects occur without detectable reduction in chromosome-bound cohesin, we propose that the dynamic behavior of the complex, mediated by PDS5 proteins, is key for successful completion of meiotic prophase I.
... Wapl also localises to chromosomes during pachynema in mouse oocytes (Zhang et al., 2008). Significantly, however, this localisation of Soronin to chromosome axes occurs sometime after pre-meiotic S-phase (Jordan et al., 2017) contrasting with the close temporal association between Soronin association and DNA replication in mitosis (Lafont et al., 2010;Nishiyama et al., 2010). Furthermore, Soronin localisation during meiosis is distinct from meiotic cohesin and more closely aligned with synapsis (Gomez et al., 2016;Jordan et al., 2017). ...
... Significantly, however, this localisation of Soronin to chromosome axes occurs sometime after pre-meiotic S-phase (Jordan et al., 2017) contrasting with the close temporal association between Soronin association and DNA replication in mitosis (Lafont et al., 2010;Nishiyama et al., 2010). Furthermore, Soronin localisation during meiosis is distinct from meiotic cohesin and more closely aligned with synapsis (Gomez et al., 2016;Jordan et al., 2017). In line with this, Soronin recruitment persists in the absence of Rec8, Smc1β or Stag3 and depends instead on the synaptonemal complex transverse filament protein, Sycp1, altogether raising the possibility of a noncohesin binding partner for Soronin during meiosis (Gomez et al., 2016;Jordan et al., 2017). ...
... Furthermore, Soronin localisation during meiosis is distinct from meiotic cohesin and more closely aligned with synapsis (Gomez et al., 2016;Jordan et al., 2017). In line with this, Soronin recruitment persists in the absence of Rec8, Smc1β or Stag3 and depends instead on the synaptonemal complex transverse filament protein, Sycp1, altogether raising the possibility of a noncohesin binding partner for Soronin during meiosis (Gomez et al., 2016;Jordan et al., 2017). It should be noted that the vast majority of work on cohesin loading and cohesion establishment referred to here has been undertaken during spermatogenesis, so it remains to be confirmed whether similar pathways apply in oocytes. ...
Background:
Meiotic chromosome segregation in human oocytes is notoriously error-prone, especially with ageing. Such errors markedly reduce the reproductive chances of increasing numbers of women embarking on pregnancy later in life. However, understanding the basis for these errors is hampered by limited access to human oocytes.
Objective and rationale:
Important new discoveries have arisen from molecular analyses of human female recombination and aneuploidy along with high-resolution analyses of human oocyte maturation and mouse models. Here, we review these findings to provide a contemporary picture of the key players choreographing chromosome segregation in mammalian oocytes and the cellular basis for errors.
Search methods:
A search of PubMed was conducted using keywords including meiosis, oocytes, recombination, cohesion, cohesin complex, chromosome segregation, kinetochores, spindle, aneuploidy, meiotic cell cycle, spindle assembly checkpoint, anaphase-promoting complex, DNA damage, telomeres, mitochondria, female ageing and female fertility. We extracted papers focusing on mouse and human oocytes that best aligned with the themes of this review and that reported transformative and novel discoveries.
Outcomes:
Meiosis incorporates two sequential rounds of chromosome segregation executed by a spindle whose component microtubules bind chromosomes via kinetochores. Cohesion mediated by the cohesin complex holds chromosomes together and should be resolved at the appropriate time, in a specific step-wise manner and in conjunction with meiotically programmed kinetochore behaviour. In women, the stage is set for meiotic error even before birth when female-specific crossover maturation inefficiency leads to the formation of at-risk recombination patterns. In adult life, multiple co-conspiring factors interact with at-risk crossovers to increase the likelihood of mis-segregation. Available evidence support that these factors include, but are not limited to, cohesion deterioration, uncoordinated sister kinetochore behaviour, erroneous microtubule attachments, spindle instability and structural chromosomal defects that impact centromeres and telomeres. Data from mice indicate that cohesin and centromere-specific histones are long-lived proteins in oocytes. Since these proteins are pivotal for chromosome segregation, but lack any obvious renewal pathway, their deterioration with age provides an appealing explanation for at least some of the problems in older oocytes.
Wider implications:
Research in the mouse model has identified a number of candidate genes and pathways that are important for chromosome segregation in this species. However, many of these have not yet been investigated in human oocytes so it is uncertain at this stage to what extent they apply to women. The challenge for the future involves applying emerging knowledge of female meiotic molecular regulation towards improving clinical fertility management.
Cohesin cofactors regulate the loading, maintenance, and release of cohesin complexes from chromosomes during mitosis but little is known on their role during vertebrate meiosis. One such cofactor is PDS5, which exists as two paralogs in somatic and germline cells, PDS5A and PDS5B, with unclear functions. Here, we have analyzed their distribution and functions in mouse spermatocytes. We show that simultaneous excision of Pds5A and Pds5B results in severe defects during early prophase I while their individual depletion does not, suggesting their functional redundancy. Shortened axial/lateral elements and a reduction of early recombination nodules are observed after the strong depletion of PDS5A/B proteins. Moreover, telomere integrity and their association to the nuclear envelope are severely compromised. As these defects occur without detectable reduction in chromosome-bound cohesin, we propose that the dynamic behavior of the complex, mediated by PDS5 proteins, is key for successful completion of meiotic prophase I.
