CDK2 regulates nuclear envelope protein dynamics and telomere attachment in mouse meiotic prophase

Viera, Alberto; Alsheimer, Manfred; Gómez, Rocío; Berenguer, Inés; Ortega, Sagrario; Symonds, Catherine E.; Santamarı́a, David; Benavente, Ricardo; Suja, José Á.

doi:10.1242/jcs.154922

Cited by 56 publications

(79 citation statements)

References 46 publications

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“…A similar defect has been described in CDK2 null spermatocytes (Viera et al 2015). These cells exhibited alterations in the nuclear envelope and detached telomeres in the nuclear space that were associated with the LINC complex protein SUN1 and with residual NE proteins (Viera et al 2015). We previously reported that both cyclin E1 and E2 interact with CDK2 and drive its localization in telomeres during pachynema and diplonema.…”

Section: Resultssupporting

confidence: 78%

E-type cyclins modulate telomere integrity in mammalian male meiosis

2015

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We have shown that E-type cyclins are key regulators of mammalian male meiosis. Depletion of cyclin E2 reduced fertility in male mice due to meiotic defects, involving abnormal pairing and synapsis, unrepaired DNA, and loss of telomere structure. These defects were exacerbated by additional loss of cyclin E1, and complete absence of both E-type cyclins produces a meiotic catastrophe. Here, we investigated the involvement of E-type cyclins in maintaining telomere integrity in male meiosis. Spermatocytes lacking cyclin E2 and one E1 allele (E1+/−E2−/−) displayed a high rate of telomere abnormalities but can progress to pachytene and diplotene stages. We show that their telomeres exhibited an aberrant DNA damage repair response during pachynema and that the Shelterin-complex proteins TRF2 and RAP2 were significantly decreased in the proximal telomeres. Moreover, the insufficient level of these proteins correlated with an increase of γ-H2AX foci in the affected telomeres, and resulted in telomere associations involving TRF1 and telomere detachment in later prophase-I stages. These results suggest that E-type cyclins are key modulators of telomere integrity during meiosis by, at least in part, maintaining the balance of Shelterin-complex proteins, and uncover a novel role of E-type cyclins in regulating chromosome structure during male meiosis.

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Section: Resultssupporting

confidence: 78%

E-type cyclins modulate telomere integrity in mammalian male meiosis

2015

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“…The kinase activity of Cdk2 on telomeres can be activated by Speedy A, but it is likely that other cyclins also activate the telomeric Cdk2, which in turn regulates telomere-led chromosome movements on the NE, possibly through phosphorylation of SUN1 (19,34). It has been reported that E-type cyclins (E1 and E2) also form complexes with Cdk2 in mouse spermatocytes, and the knockout mice for Ccne1 and Ccne2 partially mimic the phenotypes seen in Cdk2 −/− spermatocytes, suggesting the involvement of canonical cyclins in the activation of Cdk2 during meiosis (35,36).…”

Section: Discussionmentioning

confidence: 99%

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

Bayazit

Liu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Telomere attachment to the nuclear envelope (NE) is a prerequisite for chromosome movement during meiotic prophase I that is required for pairing of homologous chromosomes, synapsis, and homologous recombination. Here we show that Speedy A, a noncanonical activator of cyclin-dependent kinases (Cdks), is specifically localized to telomeres in prophase I male and female germ cells in mice, and plays an essential role in the telomere-NE attachment. Deletion of Spdya in mice disrupts telomere-NE attachment, and this impairs homologous pairing and synapsis and leads to zygotene arrest in male and female germ cells. In addition, we have identified a telomere localization domain on Speedy A covering the distal N terminus and the Cdk2-binding Ringo domain, and this domain is essential for the localization of Speedy A to telomeres. Furthermore, we found that the binding of Cdk2 to Speedy A is indispensable for Cdk2's localization on telomeres, suggesting that Speedy A and Cdk2 might be the initial components that are recruited to the NE for forming the meiotic telomere complex. However, Speedy A-Cdk2-mediated telomere-NE attachment is independent of Cdk2 activation. Our results thus indicate that Speedy A and Cdk2 might mediate the initial telomere-NE attachment for the efficient assembly of the telomere complex that is essential for meiotic prophase I progression. meiosis | telomere | Speedy A | Cdk2 | germ cells

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“…Telomere attachment to SUN1 is regulated by phosphorylation of the SUN1 N-terminal domain in both mouse (Ortega et al, 2003; Viera et al, 2015; Viera et al, 2009) and in C. elegans (Penkner et al, 2009). SUN1 phosphorylation is induced in mice by the Cyclin-dependent kinase, Cdk2.…”

Section: The Zygotene Chromosomal Bouquetmentioning

confidence: 99%

“…SUN1 phosphorylation is induced in mice by the Cyclin-dependent kinase, Cdk2. cdk2 −/− mice are viable, but sterile, and in mutant spermatocytes and oocytes, telomeres do not localize to SUN1 on the NE and synapsis is abrogated (Ortega et al, 2003; Viera et al, 2015; Viera et al, 2009). Importantly, Cdk2 purified from testes was shown to phosphorylate the N-terminus of SUN1 in vitro (Viera et al, 2015).…”

Section: The Zygotene Chromosomal Bouquetmentioning

confidence: 99%

Coordination of cellular differentiation, polarity, mitosis and meiosis – New findings from early vertebrate oogenesis

Elkouby

Mullins

2017

Developmental Biology

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A mechanistic dissection of early oocyte differentiation in vertebrates is key to advancing our knowledge of germline development, reproductive biology, the regulation of meiosis, and all of their associated disorders. Recent advances in the field include breakthroughs in the identification of germline stem cells in Medaka, in the cellular architecture of the germline cyst in mice, in a mechanistic dissection of chromosomal pairing and bouquet formation in meiosis in mice, in tracing oocyte symmetry breaking to the chromosomal bouquet of meiosis in zebrafish, and in the biology of the Balbiani body, a universal oocyte granule. Many of the major events in early oogenesis are universally conserved, and some are co-opted for species-specific needs. The chromosomal events of meiosis are of tremendous consequence to gamete formation and have been extensively studied. New light is now being shed on other aspects of early oocyte differentiation, which were traditionally considered outside the scope of meiosis, and their coordination with meiotic events. The emerging theme is of meiosis as a common groundwork for coordinating multifaceted processes of oocyte differentiation. In an accompanying manuscript we describe methods that allowed for investigations in the zebrafish ovary to contribute to these breakthroughs. Here, we review these advances mostly from the zebrafish and mouse. We discuss oogenesis concepts across established model organisms, and construct an inclusive paradigm for early oocyte differentiation in vertebrates.

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CDK2 regulates nuclear envelope protein dynamics and telomere attachment in mouse meiotic prophase

Cited by 56 publications

References 46 publications

E-type cyclins modulate telomere integrity in mammalian male meiosis

E-type cyclins modulate telomere integrity in mammalian male meiosis

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

Coordination of cellular differentiation, polarity, mitosis and meiosis – New findings from early vertebrate oogenesis

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