CNTD1’s crossover act

B efore meiotic divisions, chromosomes form crossovers, which represent the reciprocal exchanges between the DNA molecules of the homolo-gous partner chromosomes. These crossovers aren't just important for reassorting genetic traits; they're essential for the correct alignment and segregation of meiotic chromosomes. To ensure that every homologous chromosome pair forms at least one cross-over—and, perhaps, to aid homologues fi nd-ing each other in the fi rst place—meiotic cells generate a vast excess of DNA double-strand breaks (DSBs), most of which are then repaired by " noncrossover " recombination pathways that restore intact DNA molecules without resulting in a crossover. Holloway et al. reveal that a cyclin-related protein called CNTD1 helps determine which DSB sites mature into crossovers and which don't (1). Mouse spermatocytes initially form around 200–300 DSBs, which are subsequently pared down to just 20–30 crossover sites. " Crossovers are placed in a specifi c manner, " explains Paula Cohen, from Cor-nell University in Ithaca, New York. " You have to have at least one on every chromosome pair, and, if there are two, they can't be too close together. So how does the cell orchestrate repair of all these DSBs at high fi delity, while ensuring that the breaks that become crossovers are distributed appropriately? " Several proteins have been identifi ed that help to specify which DSBs mature into crossovers. The MutS␥ complex (consisting of the subunits MSH4 and MSH5) binds to around half of the initial break sites, and a subset of these subsequently recruit the SUMO ligase RNF212 (2, 3). Finally, the MutL␥ complex (consisting of MLH1 and MLH3) binds to the 20–30 sites where mature crossovers form, and the excess MutS␥ sites are eliminated (4). In 2012, Rayka Yokoo and Anne Villeneuve at Stanford University identifi ed a cyclin-related protein in C. elegans named COSA-1 that is required to convert a subset of DSBs into mature crossovers and functions in conjunction with MutS␥ (5). " Whereas the MutS␥ complex is present in plants, animals, and fungi, COSA-1 orthologues are only found in animals. Thus, we felt that it was important to look at this protein in mice, " says Villeneuve. Yokoo and Villeneuve therefore collaborated with Cohen and her colleagues Kim Holloway and Xianfei Sun to examine the function of COSA-1's mouse orthologue, CNTD1 (1). CNTD1-deficient mice were infertile; male animals, for example, were unable to produce spermatozoa. Meiotic spermatocytes lacking CNTD1 generated DSBs and …