Biological Background to the Eco1 protein and the cohesin complex.

Cohesion between sister chromatids is established during S-phase and maintained through G2 phase of cell cycle until it is resolved in anaphase of mitosis. Considerable progress has been made in the identification of the proteins that hold the chromatids together and proteins that are required for regulation of their separation during cell division [for review see [1-3]]. In Saccharomyces cerevisiae, a complex consisting of Scc1, Smc1, Smc3 and Scc3 proteins, called cohesin, ensures the connection between sister chromatids [4-6]. Similar complexes were demonstrated to exist in Xenopus oocytes [7, 8] and in human cells [8, 9]. The resolution of cohesion in yeast is achieved through the cleavage of Scc1 by a protease, Esp1 (separase), whose activity is regulated by an additional subunit, securin, Pds1 [10-12]. However, the mechanism that leads to the establishment of cohesion remains unknown.
Apart from the components of the cohesin complex per se, a number of additional proteins were implicated in establishment and maintenance of cohesion in budding yeast and in some cases homologous proteins have been identified in other organisms. These include the loading factors Scc2 and Scc4 (adherin complex) that are required for cohesin binding to DNA [13, 14], a specific DNA polymerase k, or Trf4 [15], a component of a novel RF-C-like complex, Ctf18, a chromatin-associated factor, Ctf4 [16], and a protein required for establishment and maintenance of cohesion, Pds5 [9, 17-19].
Eco1 (Ctf7) is the only essential protein that is known to be absolutely required for linking the newly replicated DNA molecules together during S phase but not required for subsequent maintenance of cohesion [6, 20] in S. cerevisiae (its homologue in Schizosaccharomyces pombe is Eso1 [21]). Genetic interactions point to the functional association of Eco1 with the components of the DNA replication machinery. The temperature-sensitive allele eco1 is synthetically lethal (i) with a mutation in POL30 which encodes the DNA polymerase processivity factor, proliferating cell nuclear antigen (PCNA), and (ii) with a deletion of Ctf18 encoding an RF-C-like protein [20]. RF-C complexes are responsible for loading PCNA onto DNA. The temperature-sensitivity caused by eco1 is also partially suppressed by overexpression of POL30 [20]. The same result was observed with Eco1 and POL30 homologues in S. pombe [21]. In addition, the temperature sensitivity of the eso1 mutant strain was partially rescued by overexpression of the carboxy-terminal one-third of DNA polymerase e devoid of the catalytic domain but presumably responsible for its cell cycle check point regulatory activity [21].


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