Abstract
Several lines of evidence suggest the existence in the eukaryotic cells of a tight, yet largely unexplored, connection between DNA replication and sister chromatid cohesion. Tethering of newly duplicated chromatids is mediated by cohesin, an evolutionarily conserved hetero-tetrameric protein complex that has a ring-like structure and is believed to encircle DNA. Cohesin is loaded onto chromatin in telophase/G1 and converted into a cohesive state during the subsequent S phase, a process known as cohesion establishment. Many studies have revealed that down-regulation of a number of DNA replication factors gives rise to chromosomal cohesion defects, suggesting that they play critical roles in cohesion establishment. Conversely, loss of cohesin subunits (and/or regulators) has been found to alter DNA replication fork dynamics. A critical step of the cohesion establishment process consists in cohesin acetylation, a modification accomplished by dedicated acetyltransferases that operate at the replication forks. Defects in cohesion establishment give rise to chromosome mis-segregation and aneuploidy, phenotypes frequently observed in pre-cancerous and cancerous cells. Herein, we will review our present knowledge of the molecular mechanisms underlying the functional link between DNA replication and cohesion establishment, a phenomenon that is unique to the eukaryotic organisms.
Highlights
A comprehensive analysis carried out in the Yu laboratory revealed that in synchronized HeLa cells cohesin is loaded onto chromatin by the Scc2-Scc4 loader complex at sites adjacent to those occupied by the pre-replication complexes (pre-RCs) in a process that is dependent on the activity of dependent kinase (DDK) [33]
Cohesion establishment requires the conversion of a “dynamic” form of cohesin bound to a single chromatid to a “cohesive” acetylated form of cohesin bound to the two sister chromatids
Taking advantage of the presence of a PK-tag on the Scc1 subunit, cross-linked cohesin rings could be immunoprecipitated from the cell extracts and their association with one or two mini-chromosomes could be assessed by gel electrophoresis: CDs structures could only derive from a cohesin conversion mechanism in yeast cells where de novo loading is not functional
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Loading/unloading reactions were analyzed in vitro using budding yeast purified cohesin, Scc2-Scc and Pds5-Wapl complexes [11,12,13] These elegant biochemical studies carried out by Murayama in Uhlmann laboratory revealed that both cohesin loading and releasing processes require the Smc1-Smc ATPase activity and suggest that chromatids may follow a similar path during transport into or out of the cohesin ring. Other studies revealed the importance of an additional cohesin gate, the one formed by the Smc hinge (named “hinge gate”) and suggested an alternative mechanism of DNA entrapment that involves opening of the “hinge gate” [14,15] This model is mainly based on the observation that in budding yeast cells a rapamycin-mediated artificial fusion of Smc with Scc, which blocks the “kleisin. A comprehensive analysis carried out in the Yu laboratory revealed that in synchronized HeLa cells cohesin is loaded onto chromatin by the Scc2-Scc loader complex at sites adjacent to those occupied by the pre-RCs in a process that is dependent on the activity of DDK [33]
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