Ataxia telangiectasia mutated expression and activation in the testis.
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.
Hamer
Geert
G
Department of Endocrinology, Faculty of Biology, Utrecht University, 3584 CH Utrecht, The Netherlands. geert.hamer@cgb.ki.se
Kal
Henk B
HB
Westphal
Christoph H
CH
Ashley
Terry
T
de Rooij
Dirk G
DG
D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D008297:Male; D008540:Meiosis; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010766:Phosphorylation; D011418:Prophase; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D013090:Spermatocytes / Q000502:physiology; D013093:Spermatogonia / Q000502:physiology; D013737:Testis / Q000378:metabolism* / Q000528:radiation effects; D014018:Tissue Distribution; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases