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

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.

Temperature-dependent regulation of rDNA condensation inSaccharomyces cerevisiae

“…Chromatin condensation and the arrangement of chromosomes within the nuclear volume are collectively mediated by cohesin- and condensin-dependent DNA segment tetherings that occur in either cis (within a single DNA molecule) or trans (between separate DNA molecules) conformations 1,2 . Recent evidence is consistent with the notion that cis DNA tetherings established during interphase are critical for the proper deployment of developmental transcription programs 3,4 .…”

“…Condensins in addition introduce positive supercoils into chromatin, promotes complementary single strand DNA reannealing and facilitates DNA catenation resolution 66 . Cohesin-dependent tethering of DNA segments is also critical for transcription regulation, nuclear architecture and sister chromatid tethering 1 . A final mechanism of hypercondensation could involve heat shock proteins, 67 which may act in coordination or in parallel to the recruitment of condensins and cohesins (Fig.…”

“…All of these studies operate under the assumption that mitotic chromatin structures in wildtype cells are refractory to the temperature shift required to inactivate conditional allele gene products. Conversely, a growing body of evidence suggests that DNA segment cis and trans tethers of interphase cells remain dynamic to respond to external cues 1-5,33 . Here, we developed a streamlined rDNA condensation assay and report that wildtype budding yeast exhibit a mitotic chromatin hypercondensation activity that is induced at temperatures typically used to inactivate conditional alleles.…”

Polyteny: still a giant player in chromosome research

“…The cohesin complex has a critical role in regulating the structure of chromosomes in dividing cells especially during mitosis where it is responsible for holding together sister chromatids (Skibbens 2016; Nasmyth and Haering 2009). Cohesins are also dynamic on chromatin during interphase, including on polytene chromosomes.…”

Multiple Determinants and Consequences of Cohesion Fatigue in Mammalian Cells

“…The precise molecular nature of how Cohesin holds sister chromatids together remains controversial. Most concepts are specific variations on two general modes of Cohesin/chromatin interaction termed "embrace" or "handcuff" models, reviewed in (Skibbens, 2016). Embrace models propose that both sisters are contained within the same Cohesin ring, while handcuff models suggest each sister chromatid is enclosed in separate rings that are bound together.…”