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This Article Full Text Full Text (PDF) All Versions of this Article: 70/4/1206    most recent biolreprod.103.024950v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal My Folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hamer, G. Articles by de Rooij, D. G. Search for Related Content PubMed PubMed Citation Articles by Hamer, G. Articles by de Rooij, D. G. Agricola Articles by Hamer, G. Articles by de Rooij, D. G.

Ataxia Telangiectasia Mutated Expression and Activation in the Testis¹

Department of Endocrinology,³ Faculty of Biology, Utrecht University, 3584 CH Utrecht, The Netherlands Department of Cell Biology,⁴ UMCU, 3584 CX Utrecht, The Netherlands Department of Radiotherapy,⁵ UMCU, 3584 CX Utrecht, The Netherlands Polaris Venture Partners,⁶ Waltham, Massachusetts 02451 Department of Genetics,⁷ Yale University School of Medicine, New Haven, Connecticut 06510

Ionizing radiation (IR) and consequent induction of DNA double-strand breaks (DSBs) causes activation of the protein ataxia telangiectasia mutated (ATM). Normally, ATM is present as inactive dimers; however, in response to DSBs, the ATM dimer partners cross-phosphorylate each other on serine 1981, and kinase active ATM monomers are subsequently released. We have studied the presence of both nonphosphorylated as well as active serine 1981 phosphorylated ATM (pS1981-ATM) in the mouse testis. In the nonirradiated testis, ATM was present in spermatogonia and spermatocytes until stage VII of the cycle of the seminiferous epithelium, whereas pS1981-ATM was found only to be present in the sex body of pachytene spermatocytes. In response to IR, ATM became activated by pS1981 cross-phosphorylation in spermatogonia and Sertoli cells. Despite the occurrence of endogenous programmed DSBs during the first meiotic prophase and the presence of ATM in both spermatogonia and spermatocytes, pS1981 phosphorylated ATM did not appear in spermatocytes after treatment with IR. These results show that spermatogonial ATM and ATM in the spermatocytes are differentially regulated. In the mitotically dividing spermatogonia, ATM is activated by cross-phosphorylation, whereas during meiosis nonphosphorylated ATM or differently phosphorylated ATM is already active. ATM has been shown to be present at the synapsed axes of the meiotic chromosomes, and in the ATM knock-out mice spermatogenesis stops at pachytene stage IV of the seminiferous epithelium, indicating that indeed nonphosphorylated ATM is functional during meiosis. Additionally, ATM is constitutively phosphorylated in the sex body where its continued presence remains an enigma.

¹ Supported by the J.A. Cohen Institute for Radiopathology and Radiation Protection, Leiden, The Netherlands, and NIH grant R01-HD39384.

² Correspondence: Geert Hamer, Center for Genomics and Bioinformatics (CGB), Karolinska Institutet, Berzelius väg 35, SE-171 77 Stockholm, Sweden. FAX: 46 8 32 36 79; geert.hamer{at}cgb.ki.se

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