Especificidad funcional de los factores de cohesión Pds5A y Pds5B

Resumen

Chromosome segregation is a crucial event in cell proliferation. One of the mechanisms that ensures its accuracy is sister chromatid cohesion mediated by cohesin. This multiprotein complex, conserved from yeast to human, is composed of four subunits: SMC1, SMC3, Scc1 (or Mcd1/Rad21) and Scc3 (or SA). Cohesin acts by entrapping the sister chromatids within its ring-shaped structure. A number of factors modulate the interaction of cohesin with chromatin throughout the cell cycle. Some of them interact transiently with the complex to promote its binding to chromatin in G1 phase, the establishment of cohesion upon DNA replication in S phase or the dissociation of cohesin from chromatin in mitosis. Others, like Pds5, Wapl and Sororin, are more stably bound to cohesin and modulate its dynamic association with chromatin. In particular, Pds5 is essential for the stable association of cohesin with chromatin in yeast whereas in higher eukaryotes Pds5 is also required for proper unloading of cohesin during mitotic prophase. In vertebrates there are two homologs of Pds5, Pds5A and Pds5B, but their specific functions are unclear. We have generated the conditional knockout mice for both Pds5A and Pds5B to address their specific role in cohesion and the significance of their functions in the context of an organism. Complete ablation of either Pds5 protein results in embryonic lethality while heterozygous mice have no phenotype. We found that Pds5B is specifically required for centromeric cohesion, with Pds5A being more relevant for arm and telomere cohesion. Elimination of either Pds5 protein decreases Smc3 acetylation, a crucial step in cohesion establishment. In particular, we found that Pds5B is necessary for the accumulation of cohesin acetyl transferase Esco2 at the late replicating centromeric heterochromatin and this, in turn, prevents recruitment of Sororin to this region. As a consequence, centromeric cohesion is not established properly. Pds5B null cells can nevertheless progress through mitosis and align their chromosomes, showing no significant delay in prometaphase. However, chromosome biorientation and segregation is faulty and often leads to aneuploidy that can be observed both in cultured fibroblast and in fetal liver cells. None of these chromosome segregation defects are found in Pds5A null cells.