Of Rings and Rods: Regulating Cohesin Entrapment of DNA to Generate Intra- and Intermolecular Tethers.

Robert V Skibbens,Mónica P Colaiácovo

doi:10.1371/journal.pgen.1006337

Abstract

The clinical relevance of cohesin in DNA repair, tumorigenesis, and severe birth defects continues to fuel efforts in understanding cohesin structure, regulation, and enzymology. Early models depicting huge cohesin rings that entrap two DNA segments within a single lumen are fading into obscurity based on contradictory findings, but elucidating cohesin structure amid a myriad of functions remains challenging. Due in large part to integrated uses of a wide range of methodologies, recent advances are beginning to cast light into the depths that previously cloaked cohesin structure. Additional efforts similarly provide new insights into cohesin enzymology: specifically, the discoveries of ATP-dependent transitions that promote cohesin binding and release from DNA. In combination, these efforts posit a new model that cohesin exists primarily as a relatively flattened structure that entraps only a single DNA molecule and that subsequent ATP hydrolysis, acetylation, and oligomeric assembly tether together individual DNA segments.

Highlights

While simple in concept, the binding together of two or more DNA segments is critical to ensure human health
DNA interactions between sister chromatids both identify chromatids as sisters to ensure high fidelity chromosome segregation and provide access to template DNA required for error-free repair of double-strand breaks (Fig 1)
Condensins were predominantly folded over to promote hinge–head associations, but rings and lassos were observed. Whether such intermediate structures are predicated on the dynamics of partially disrupted and flexible complexes or represent functional cycles remains unknown [44]

Summary

Introduction

The binding together of two or more DNA segments is critical to ensure human health. Condensins were predominantly folded over to promote hinge–head associations, but rings and lassos (dissociated heads in which only one appeared bound to the hinge) were observed Whether such intermediate structures are predicated on the dynamics of partially disrupted and flexible complexes (having survived extractions and enrichments) or represent functional cycles (despite conformation changes that occur in the absence of DNA and ATP) remains unknown [44]. Chromatin-retained cohesins in pds5-inactivated cells retain their acetylation state (a modification that occurs only during S phase), negating arguments that the detected cohesins involved newly loaded (i.e., during mitosis) complexes [33] This reemerging model of cohesion establishment—that cohesins stably deposited onto each sister chromatid are subsequently converted to a tethering-competent, higher-order structure [57]—suggests that sister chromatid tethering requires multiple transition states that are likely regulated by both cohesin ATP hydrolysis and Eco1/Ctf7-dependent acetylation. How ATP binding and hydrolysis and acetylation impact deposition and stability remain exciting frontiers in cohesin research

A New Role for ATP Hydrolysis

Findings

Conclusion