title: ATM and RPA in meiotic chromosome synapsis and recombination.
abstract: ATM is a member of the phosphatidylinositol 3-kinase (PIK)-like kinases, some of which are active in regulating DNA damage-induced mitotic cell-cycle checkpoints. ATM also plays a role in meiosis. Spermatogenesis in Atm-/- male mice is disrupted, with chromosome fragmentation leading to meiotic arrest; in human patients with ataxia-telangiectasia (A-T), gonadal atrophy is common. Immuno-localization studies indicate that ATM is associated with sites along the synaptonemal complex (SC), the specialized structure along which meiotic recombination occurs. Recombination, preceded by pairing of homologous chromosomes, is thought to require heteroduplex formation between homologous DNA, followed by strand exchange. These early meiotic steps (entailing the formation and processing of meiotic recombination intermediates with DNA-strand interruptions) require ssDNA-binding proteins such as replication protein A (RPA; refs 5-7). In somatic cells, DNA damage induces ATM-dependent phosphorylation of RPA. We demonstrate here that ATM and RPA co-localize along synapsed meiotic chromosomes and at sites where interactions between ectopic homologous chromosome regions appear to initiate. In Atm-/- meiotic prophase spermatocytes, immuno-localization shows that RPA is present along synapsing chromosomes and at sites of fragmentation of the SC. These results suggest that RPA and ATM co-localize at sites where interhomologous-DNA interactions occur during meiotic prophase and where breaks associated with meiotic recombination take place after synapsis, implying a possible functional interaction between these two proteins.
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Plug
authors.forename: A H
authors.initials: AH
authors.lastname: Peters
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: K S
authors.initials: KS
authors.lastname: Keegan
authors.forename: M F
authors.initials: MF
authors.lastname: Hoekstra
authors.forename: D
authors.initials: D
authors.lastname: Baltimore
authors.forename: P
authors.initials: P
authors.lastname: de Boer
authors.forename: T
authors.initials: T
authors.lastname: Ashley
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D053938:DNA Fragmentation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011418:Prophase / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D011995:Recombination, Genetic; D051716:Replication Protein A; D013090:Spermatocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D013573:Synaptonemal Complex / Q000235:genetics; D025521:Tumor Suppressor Proteins
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D051716:Replication Protein A; D025521:Tumor Suppressor Proteins; C497167:RPA1 protein, human; C497168:Rpa1 protein, mouse; C576324:ATM protein, human; C576325:Atm protein, mouse