ATM AND RPA IN MEIOTIC CHROMOSOME SYNAPSIS AND RECOMBINATION

ATM is a member of the phosphatidylinositol 3-kinase (PIK)-like kinase s, some of which are active in regulating DNA damage-induced mitotic c ell-cycle checkpoints(1,2). ATM also plays a role in meiosis, Spermato genesis in Atm(-/-)male mice is disrupted, with chromosome fragmentati on leading to meiotic arrest(3): in human patients with ataxia-telangi ectasia (A-T), gonadal atrophy is common. Immune-localization studies indicate that ATM is associated with sites along the synaptonemal comp lex (SC), the specialized structure along which meiotic recombination occurs(4). Recombination, preceded by pairing of homologous chromosome s, is thought to require heteroduplex formation between homologous DNA , followed by strand exchange. These early melotic steps (entailing th e formation and processing of meiotic recombination intermediates with DNA-strand interruptions) require ssDNA-binding proteins such as repl ication protein A (RPA; refs 5-7). In somatic cells, DNA damage induce s ATM-dependent phosphorylation of RpA(8,9). We demonstrate here that ATM and RPA co-localize along synapsed meiotic chromosomes and at site s where interactions between ectopic homologous chromosome regions app ear to initiate. In Atm(-/-)meiotic prophase spermatocytes, immune-loc alization 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 recom bination take place after synapsis, implying a possible functional int eraction between these two proteins.