Cohesin subunit Rad21L, the new kid on the block has new ideas.

Sexual reproduction is one of the great success stories of evolution, allowing the reshuffling of genetic material from two parents to create new gene combinations for the next generation. to this end, diploid organisms produce gametes containing a randomly selected haploid comple ment of their genome. the necessary chromosome gymnastics occur in two sequential meiotic cell divisions (petronczki et al, 2003). the first ‘reductional’ division separates the two parental homologues, thereby reducing the number of chromosomes by one-half. a second ‘equational’ division splits each homologue into its two sister chromatids. chromosome behaviour in both divisions is influenced by the chromosomal cohesin complex, which links sister chromatids and mediates their regulated separation. the cohesin complex has been the subject of intense investigation for 14 years and, thus, the identification of a hitherto unknown subunit—by Watanabe and colleagues in EMBo reports, and by lee and Hirano in a recent issue of the Journal of Cell Biology (ishiguro et al, 2011; lee & Hirano, 2011)—comes as a surprise. cohesin is a ring-shaped protein complex that was initially characterized on mitotic chromosomes. it consists of four core subunits: two from the structural maintenance of chromosomes (Smc) family, Smc1 and Smc3; rad21, which is also known as Scc1; and Scc3, which has two mammalian paralogues—Sa1 and Sa2. the Smc subunits form most of the ring circumference, whereas the other two stabilize it and probably regulate its function (Fig 1a). cohesin is loaded onto chromosomes in the g1 phase of the cell cycle and establishes sister chromatid cohesion in S-phase by topologically entrapping the two newly synthesized replication products. it embraces sister chromatids until mitosis; at anaphase onset, proteolytic cleavage of the rad21Scc1 subunit opens the ring to release sister chromatids (uhlmann, 2009). During meiosis, this is extended in preparation for the first reductional division and, in most organisms, rad21Scc1 is mostly replaced by a meiosisspecific paralogue, rec8. Vertebrates express additional meiosis-specific variants of Smc1 (Smc1β) and Scc3 (Sa3). after pre-meiotic Dna replication, meiotic cohesins promote homologue recombination; the basis for genetic exchange between maternal and paternal genomes. the cohesin complex binds to the ‘lateral elements’ of the synaptonemal complex, which joins the two homologous pairs of sister chromatids to form the characteristic pachytene chromosomes of meiotic prophase (Fig 1B). once recombination is complete, the synapto nemal complex disassembles, whereas the two homologous chromosomes remain connected by sister chromatid cohesion, distal to the sites of homologue exchange. at least, that was the picture until the discovery of an additional paralogue of rad21Scc1 and rec8 in vertebrates (ishiguro et al, 2011; lee & Hirano, 2011). Due to its similarity to rad21Scc1, it has been called rad21l (for ‘rad21-like’). rad21l is expressed exclusively in cells undergoing meiosis and forms a complex with the other meiosis-specific cohesin subunits (Fig 1a). We cannot be sure of the function of rad21l, as the development of genetic tools in recombinant mouse strains will take time. nevertheless, features of the localization pattern of rad21l have led the authors to speculate about its role. Similarly to rec8, rad21l appears on chromosomes at premeiotic S-phase, as would be expected for cohesin subunits that establish sister chromatid cohesion. Surprisingly, once recombination is complete, rad21l disappears from chromo somes, while homologues remain juxtaposed by the synaptonemal complex and rec8 persists along chromosome axes. thus, the rad21l complex is present on chromosomes during the establishment of sister chromatid cohesion, homologue pairing and synapsis. However, when cells approach division, rad21l has left the chromo somes, thus a role in sister chromatid cohesion is unlikely. Might rad21l have a role in homologue pairing? Both studies also highlight the exchange of rad21l for rad21Scc1 during meiotic prophase, long after the establishment of replicationcoupled cohesion (prieto et al, 2004). can rad21Scc1 substitute for rad21l in sister chromatid cohesion? Might rad21Scc1 promote chromo some condensation rather than sister chromatid cohesion? Several events contribute to homologue pairing during meiotic prophase, but the molecular basis of homologue recognition is poorly understood (Bhalla & Dernburg, 2008). Strikingly, when Watanabe and colleagues and lee and Hirano visualized rad21l along meiotic chromosomes, they found a pattern that alternates with rec8. the rad21l–rec8 pattern appears unique to each chromosome, but is reproducible along the two homologues, leading Watanabe and colleagues to suggest it could provide a ‘barcode’ for homologue recognition (Fig 1B). While this is an attractive idea, how might rad21l-containing cohesin complexes on the two homologues recognize each other? no convincing evidence has been obtained so far of interactions between more than one cohesin complex. instead, lee and Hirano provide a piece of molecular evidence that could be crucial. they find that rad21l—but not rec8 or rad21Scc1— interacts biochemically with the synaptonemal-complex protein Sycp1, which constitutes its axial element (liu et al, 1996). after trial and error Cohesin subunit Rad21L, the new kid on the block has new ideas