The ancient and evolving roles of cohesin in gene expression and DNA repair

Abstract

The cohesin complex, named for its key role in sister chromatid cohesion, also plays critical roles in gene regulation and DNA repair. It performs all three functions in single cell eukaryotes such as yeasts, and in higher organisms such as man. Minor disruption of cohesin function has significant consequences for human development, even in the absence of measurable effects on chromatid cohesion or chromosome segregation. Here we survey the roles of cohesin in gene regulation and DNA repair, and how these functions vary from yeast to man.

Figure 1. Cohesin structure and cell cycle regulation

(A) A schematic representation of the cohesin complex and its subunits. (B) An overview of cohesin chromatin loading, and removal from chromosomes, as well as cohesion establishment during an unperturbed cell cycle. Main steps during the cohesion cycle and species differences are highlighted, for further details see the main text, Phosphorylation (P), Acetylation (Ac).

Figure 2. Roles of cohesin in gene expression

In S. cerevisiae cohesin regulates genes by controlling their positioning within the nucleus, including proximity to the nucleolus and tDNA clusters. In S. pombe cohesin interacts with the Swi6 heterochromatin protein and together they regulate subtelomeric genes and increase transcriptional termination between convergent genes. In Drosophila, and likely vertebrates, cohesin and adherin selectively bind genes with promoter-proximal paused RNA polymerase (Pol II) that also bind the DSIF and NELF pausing complexes. In a context and gene-specific manner, cohesin and adherin modulate transition of Pol II to elongation by unknown mechanisms. Adherin and cohesin facilitate enhancer-promoter looping, and can counteract silencing by Polycomb Group proteins, and more rarely, cooperate with Polycomb proteins to restrain, but not silence genes. In vertebrates, cohesin has likely substituted for other CTCF cofactors seen in Drosophila, and directly interacts with CTCF to facilitate looping between CTCF binding sites, which can contribute to transcription repression, activation and insulation.

Figure 3. Functions for Cohesin in DNA damage responses, DNA repair and genome integrity

The different DNA damage response and repair actions that cohesin has been shown to be involved in are indicated in relation to the cell cycle. For further details see the main text, Phosphorylation (P), Acetylation (Ac).