Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4

Wu, Joy Y.; Ribar, Thomas J.; Cummings, David E.; Burton, Kimberly A.; McKnight, G. Stanley; Means, Anthony R.

doi:10.1038/78153

Cited by 203 publications

(152 citation statements)

References 25 publications

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“…Also, proper posttranslational modifications of protamines appear essential. Camk4, a multifunctional serine/threonine protein kinase may play a role in the exchange of TPs to protamine, as CAMK4 phosphorylates PRM2 in vitro and Camk4-null mice demonstrated prolonged retention of TP2 [Wu et al 2000]. Moreover, the final step of this chromatin remodeling, the creation of inter-and intra-molecule disulfide bonds, is also known to affect fertility as suggested by the higher sensitivity of DNA damage of marsupial spermatozoa that do not possess such a capacity [Bennetts and Aitken 2005].…”

Section: Protaminesmentioning

confidence: 99%

Spermiogenesis and DNA Repair: A Possible Etiology of Human Infertility and Genetic Disorders

Leduc¹,

Nkoma²,

Boissonneault³

2008

Systems Biology in Reproductive Medicine

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This paper reviews the possible origin of sperm DNA fragmentation and focuses on the nuclear events associated with spermiogenesis as a potential source of genetic instability and reduced fertilizing potential of the mature male gamete. Recent findings suggest a programmed DNA fragmentation and DNA damage response during the chromatin remodeling steps in spermatids. We also discuss the spermatid DNA repair mechanisms and the possible involvement of condensing proteins, such as transition proteins and protamines, in the process, as this DNA fragmentation is normally not found in late spermatids. We propose that alterations in the chromatin remodeling steps or DNA repair in elongating spermatids may lead to persistent DNA breaks. This vulnerable step of spermiogenesis may provide a clue to the etiology of sperm DNA fragmentation associated with infertility in humans. This vulnerability is further emphasized given the haploid character of spermatids that must resolve programmed double-stranded breaks by an error-prone DNA repair mechanism. Therefore, spermiogenesis has probably been overlooked as an important source of genetic instability.

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Section: Protaminesmentioning

confidence: 99%

Spermiogenesis and DNA Repair: A Possible Etiology of Human Infertility and Genetic Disorders

Leduc¹,

Nkoma²,

Boissonneault³

2008

Systems Biology in Reproductive Medicine

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“…Isoforms of CaMK are present in the flagellum of mammalian sperm and CaMK inhibitors reduce sperm motility (Wu et al 2000;Ignotz and Suarez 2005;Marin-Briggiler et al 2005). Based on this, it seems likely that the effects of CaM on motility are achieved through one or more isoforms of CaMK in the flagellum (Fig.…”

Section: Downstream Components Of Calcium Signallingmentioning

confidence: 99%

Moving to the beat: a review of mammalian sperm motility regulation

Turner¹

2006

Reprod. Fertil. Dev.

245

184

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Abstract. Because it is generally accepted that a high percentage of poorly motile or immotile sperm will adversely affect male fertility, analysis of sperm motility is a central part of the evaluation of male fertility. In spite of its importance to fertility, poor sperm motility remains only a description of a pathology whose underlying cause is typically poorly understood. The present review is designed to bring the clinician up to date with the most current understanding of the mechanisms that regulate sperm motility and to raise questions about how aberrations in these mechanisms could be the underlying causes of this pathology.

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“…A number of protein kinases are expressed in testis, and several of them are essential for male fertility (3). For example, disruption of the Camk4 which is involved in postmeiotic chromatin condensation, results in impaired spermiogenesis and male sterility (4). Targeted deletion of the casein kinase 2␣Ј catalytic subunit leads to oligozoospermia and extensive degeneration of germ cells at all stages of spermatogenesis (5), and Cdk2 is essential for completing mitotic division in germ cells (6).…”

mentioning

confidence: 99%

Identification of a Novel HSP70-binding Cochaperone Critical to HSP90-mediated Activation of Small Serine/Threonine Kinase

Jha

Wong

Zerfas

et al. 2010

Journal of Biological Chemistry

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We previously reported the identification of small serine/ threonine kinase (SSTK) that is expressed in postmeiotic germ cells, associates with HSP90, and is indispensable for male fertility. Sperm from SSTK-null mice cannot fertilize eggs in vitro and are incapable of fusing with eggs that lack zona pellucida. Here, using the yeast two-hybrid screen, we have discovered a novel SSTK-interacting protein (SIP) that is expressed exclusively in testis. The gene encoding SIP is restricted to mammals and encodes a 125-amino acid polypeptide with a predicted tetratricopeptide repeat domain. SIP is co-localized with SSTK in the cytoplasm of spermatids as they undergo restructuring and chromatin condensation, but unlike SSTK, is not retained in the mature sperm. SIP binds to SSTK with high affinity (K d ϳ10 nM), and the proteins associate with each other when co-expressed in cells. In vitro, SIP inhibited SSTK kinase activity, whereas the presence of SIP in cells resulted in enzymatic activation of SSTK without affecting Akt or MAPK activity. SIP was found to be associated with cellular HSP70, and analyses with purified proteins revealed that SIP directly bound HSP70. Importantly, SSTK recruited SIP onto HSP90, and treatment of cells with the specific HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, completely abolished SSTK catalytic activity. Hence, these findings demonstrate that HSP90 is essential for functional maturation of the kinase and identify SIP as a cochaperone that is critical to the HSP90-mediated activation of SSTK.Protein phosphorylation plays important roles during spermatogenesis (1, 2). A number of protein kinases are expressed in testis, and several of them are essential for male fertility (3). For example, disruption of the Camk4 which is involved in postmeiotic chromatin condensation, results in impaired spermiogenesis and male sterility (4). Targeted deletion of the casein kinase 2␣Ј catalytic subunit leads to oligozoospermia and extensive degeneration of germ cells at all stages of spermatogenesis (5), and Cdk2 is essential for completing mitotic division in germ cells (6). Three members of the testis-specific serine threonine kinase (TSSK) 2 family, namely TSSK1, TSSK2, and the small serine/threonine kinase (SSTK, also known as TSSK6), are expressed postmeiotically and are essential for male fertility (7-13).SSTK is one of the smallest protein kinases, consists only of N-and C-lobes of a kinase catalytic domain, and forms stable associations with heat shock protein (HSP) 70 and 90 (7). Targeted deletion of Sstk in mice resulted in male infertility without any other visible somatic defects. SSTK-null sperm could not fertilize eggs in vitro and are incapable of fusing with eggs that lack zona pellucida (9). SSTK expression first appears in elongating spermatids as they undergo cellular remodeling and chromatin condensation, and the kinase is retained in mature sperm. However, the in vivo substrate(s) for SSTK, the mechanism of activation, and the specific function that SSTK performs in spe...

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Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4

Cited by 203 publications

References 25 publications

Spermiogenesis and DNA Repair: A Possible Etiology of Human Infertility and Genetic Disorders

Spermiogenesis and DNA Repair: A Possible Etiology of Human Infertility and Genetic Disorders

Moving to the beat: a review of mammalian sperm motility regulation

Identification of a Novel HSP70-binding Cochaperone Critical to HSP90-mediated Activation of Small Serine/Threonine Kinase

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