Atm-dependent interactions of a mammalian Chk1 homolog with meiotic chromosomes

Flaggs, G.; Plug, Annemieke W.; Dunks, K.M.; Mundt, Kirsten; Ford, Jon C.; Quiggle, M.R.; Taylor, Elaine M.; Westphal, Christoph H.; Ashley, Terry; Hoekstra, Merl F.; Carr, Antony

doi:10.1016/s0960-9822(06)00417-9

Cited by 96 publications

(76 citation statements)

References 49 publications

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“…Whether the weak expression seen in some spermatocytes re¯ects any residual function of Chk2 in meiosis, or rather traces of the long-lived Chk2 protein after its function in spermatogonia had been ful®lled, remains to be elucidated. In any case, the expression pattern of Chk2 detected here contrasts with that of Chk1, a partly functionally overlapping yet structurally unrelated checkpoint kinase (Zhou and Elledge, 2000), which accumulates in late zygotene and pachytene spermatocytes and localizes to synapsed meiotic chromosomes, suggesting its possible involvement in monitoring the processing of meiotic recombination (Flaggs et al, 1997). Our data reveal also another striking di erence between Chk2, abundant even in many nonproliferating and di erentiated cells (this study), and the Chk1 protein known to be absent in quiescent and G1 phase and only expressed in S/G2/M cells during mitotic cycles (Kaneko et al, 1999).…”

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confidence: 59%

Chk2 tumour suppressor protein in human spermatogenesis and testicular germ-cell tumours

et al. 2001

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Chk2 is a transducer of DNA damage signals and a tumour suppressor whose germ-line mutations predispose to diverse tumour types. Unlike its downstream targets such as the p53 tumour suppressor, the expression patterns of Chk2 in tissues and tumours remain unknown. As DNA breaks occur commonly during gametogenesis, and p53 is wild-type and overexpressed in testicular cancer, we examined abundance and localisation of the Chk2 protein during normal development of human testes, and at various stages of germ-cell tumour (GCT) pathogenesis. Our results show that Chk2 is abundant in foetal germ cells and adult spermatogonia, yet only weakly expressed or lacking during the meiotic and later stages of spermatogenesis. High levels of Chk2 are detected in the majority of GCTs including all preinvasive carcinoma-in-situ lesions, contrary to variable expression and even lack of Chk2 in subsets of invasive GCTs and some teratoma structures, respectively. Together with our analyses of cell culture models, these results indicate that downmodulation or lack of Chk2 is not simply attributable to quiescence or di erentiation, they suggest a role for Chk2 in mitotic rather than meiotic divisions, support the concept of foetal origin of GCTs, and have implications for protein-based screening for tumour-associated aberrations of Chk2. Oncogene (2001) 20, 5897 ± 5902.

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confidence: 59%

Chk2 tumour suppressor protein in human spermatogenesis and testicular germ-cell tumours

et al. 2001

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“…In this case these proteins appear to be responding to DNA strand interruptions during the process of meiotic recombination. Chk1 has been shown to colocalize with Atr on asynapsed axes of the synaptonemal complex on murine meiotic chromosomes (Flaggs et al, 1997) and since they are both involved in G2 checkpoint control this may be a direct functional colocalization. Furthermore there is evidence using atm 7/7 mice that the synthesis or stabilization of chk1 in mouse testes is dependent on Atm, placing it downstream in G2 checkpoint control.…”

Section: Discussionmentioning

confidence: 99%

Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia-telangiectasia cells

et al. 1999

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Cells from patients with the human genetic disorder ataxia-telangiectasia (A-T) are defective in the activation of cell cycle checkpoints in response to ionizing radiation damage. In order to understand the role of ATM in checkpoint control we investigated whether Schizosaccaromyces pombe chk1, a protein kinase implicated in controlling the G2 DNA damage checkpoint, might alter the radiosensitive phenotype in A-T cells. The ®ssion yeast chk1 gene was cloned into an EBV-based vector under the control of a metallothionein promoter and transfected into A-T lymphoblastoid cells. Induction of chk1 enhanced the survival of an A-T cell line in response to radiation exposure as determined by cell viability and reduction of radiation-induced chromosome aberrations. This can be accounted for at least in part by the restoration of the G2 checkpoint to chk1 expressing cells. There was no evidence that chk1 expression corrected either the G1/S checkpoint or radioresistant DNA synthesis in S phase in these cells. These results suggest that chk1 when overexpressed acts downstream from ATM to restore the G2 checkpoint in these cells and correct the radiosensitive phenotype. These data allow us to dissociate individual checkpoint events and relate them to the radiosensitive phenotype in A-T cells.

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“…Targeted disruption of ATM, a phosphatidylinositol 3-kinase-related protein kinase homologous to the yeast DNA-damage checkpoint protein Rad3 (56), causes mouse infertility due to meiotic arrest (57)(58)(59)(60) in the early prophase I (61). A protein kinase that acts downstream to ATM is chk1, which is associated with meiotic chromosomes in mouse pachytene spermatocytes (62) and has been shown to phosphorylate and indirectly inhibit the cdc25 in yeast and mammalian mitotic cells (63)(64)(65). MPF activity and meiotic progression in spermatocytes is also regulated by temporal expression of germ cell-specific genes (66).…”

Section: Discussionmentioning

confidence: 99%

Activation of the Mitogen-activated Protein Kinase ERK1 during Meiotic Progression of Mouse Pachytene Spermatocytes

Sette

Barchi²,

Bianchini³

et al. 1999

Journal of Biological Chemistry

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Okadaic acid (OA) causes meiotic progression and chromosome condensation in cultured pachytene spermatocytes and an increase in maturation promoting factor (cyclin B1/cdc2 kinase) activity, as evaluated by H1 phosphorylative activity in anti-cyclin B1 immunoprecipitates. OA also induces a strong increase of phosphorylative activity toward the mitogen-activated protein kinase substrate myelin basic protein (MBP). Immunoprecipitation experiments with anti-extracellular signal-regulated kinase 1 (ERK1) or anti-ERK2 antibodies followed by MBP kinase assays, and direct in-gel kinase assays for MBP, show that p44/ERK1 but not p42/ERK2 is stimulated in OA-treated spermatocytes. OA treatment stimulates phosphorylation of ERK1, but not of ERK2, on a tyrosine residue involved in activation of the enzyme. ERK1 immunoprecipitated from extracts of OAstimulated spermatocytes induces a stimulation of H1 kinase activity in extracts from control pachytene spermatocytes, whereas immunoprecipitated ERK2 is uneffective. We also show that natural G 2 /M transition in spermatocytes is associated to intracellular redistribution of ERKs, and their association with microtubules of the metaphase spindle. Preincubation of cultured pachytene spermatocytes with PD98059 (a selective inhibitor of ERK-activating kinases MEK1/2) completely blocks the ability of OA to induce chromosome condensation and progression to meiotic metaphases. These results suggest that ERK1 is specifically activated during G 2 /M transition in mouse spermatocytes, that it contributes to the mechanisms of maturation promoting factor activation, and that it is essential for chromosome condensation associated with progression to meiotic metaphases.Male meiosis is a process in which a dyploid spermatocyte gives rise to four haploid round spermatids after a single round of DNA replication followed by two subsequent cell divisions. The homologous chromosomes are segregated in the two daughter cells (secondary spermatocytes) during the first meiotic division, whereas the sister chromatids, through a process resembling mitosis, are segregated during the second division to generate haploid cells. The prophase of male first meiotic division is a lengthy process which ensures the correct pairing and the crossing over between homologous chromosomes. In the mouse, this process lasts approximately 10 days, during which the homologous chromosomes become partially condensed, anneal to each other, and are maintained in proximity by a structure called the synaptonemal complex. After genetic exchange (crossing over) has occurred, the synaptonemal complex disappears and chromosome condensation allows the sites of DNA exchange to become visible as chiasmata. As for mitotic division, the nuclear envelope breaks down and microtubules are assembled into a spindle. The chromosomes become aligned to the equator of the meiotic spindle and the two sets of homologous chromosomes are separated during the anaphase. While the meiotic prophase is considerably long, metaphase and anaphase transitions ...

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Atm-dependent interactions of a mammalian Chk1 homolog with meiotic chromosomes

Cited by 96 publications

References 49 publications

Chk2 tumour suppressor protein in human spermatogenesis and testicular germ-cell tumours

Chk2 tumour suppressor protein in human spermatogenesis and testicular germ-cell tumours

Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia-telangiectasia cells

Activation of the Mitogen-activated Protein Kinase ERK1 during Meiotic Progression of Mouse Pachytene Spermatocytes

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