In addition, the molecular and physiological consequences of Bub1 up-regulation are not known

Cohesin consists of a heterodimer of the Structural Maintenance of Chromosome proteins Smc1 and Smc3, the alpha kleisin subunit Rad21/Scc1, and a protein known as Scc3 in yeast and stromal antigen in metazoa. Entrapment of the sister chromatids by cohesin allows faithful DNA repair by homologous recombination in G2 and accurate chromosome segregation during mitosis and meiosis. Cohesin’s ability to entrap two DNA segments can also act in cis to promote long-range DNA looping, which is crucial for transcriptional regulation, organization of replication Corresponding author. Mutations in cohesin and its regulators are present in at least two human syndromes, Cornelia de Lange and Roberts/SC Phocomelia, and have also been associated with tumourigenesis. A number of proteins regulate the association of cohesin with chromatin throughout the cell cycle. Cohesin is 118414-82-7 web loaded onto chromatin in G1 by the Scc2Scc4 heterodimer. Live-cell analyses have indicated that chromatin-bound cohesin is constantly turning over. Cohesin unloading depends on Wapl, whose function is particularly important during prophase in metazoa, when most cohesin is released from the condensing chromosomes. To counteract this Wapl-dependent unloading and stabilize cohesin to encircle the replicated sister chromatids, cohesin acetyl transferases must acetylate two lysine residues located in the head domain of Smc3. In vertebrates, Smc3 acetylation is accompanied by binding of Sororin to cohesin. Some evidence PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19811613 suggests that the recruitment and/or function of Wapl and Sororin depend on the HEATrepeat containing protein Pds5, although there are important differences among organisms. Pds5 provides an interaction surface for the FGF motifs present in Wapl and Sororin. The binding of Sororin to Pds5-bound cohesin after DNA replication and Smc3 acetylation has been proposed to displace Wapl, thereby stabilizing cohesin in human cells. In mitotic prophase, Sororin is released and Wapl promotes dissociation of most cohesin complexes, an action that is enhanced by cohesin phosphorylation. In vertebrate cells, multiple players in cohesion have undergone gene duplication events and subsequent divergence. Recent reports suggest that distinct cohesin variants are preferred at different regions of the chromosome. For example, cohesin complexes in somatic cells can carry the SA1 or the SA2 subunit. Cohesin-SA1 mediates telomere cohesion, cohesin-SA2 supports centromere cohesion, and both contribute to chromosome arm cohesion. Similarly, there are two CoATs in vertebrates; Esco1 and Esco2. Bulk acetylation of Smc3 depends on both CoATs, whereas local acetylation at pericentric heterochromatin depends specifically on Esco2. Finally, there are two versions of Pds5; Pds5A and Pds5B. Both proteins are B1400 amino acids long with B72% sequence homology throughout most of the protein, including the two clusters of HEAT repeats, but differing sequences in their C-terminal 300 amino acids. Currently, little is known about the functional specificity of the two Pds5 proteins. Both Pds5A and Pds5B can be found associated with either cohesin-SA1 or cohesinSA2. Previous studies have reported that knockout mice for either Pds5A or Pds5B die perinatally with several organ malformations reminiscent of CdLS, but no clear cohesion problems. Here, we report the generation of distinct knockout alleles for Pds5A and Pds5B and the analysis of mouse embryonic fibroblasts completely lacking either protein. Contrary to