Fig 1.
(A) DNA segment interactions stabilized by CTCF (transcriptional repressor) and cohesins define looped domains that aggregate into clusters of similar transcription outputs (active or silenced), termed topologically associated domains (TADs). TAD aggregation of both cis (with a single chromosome) and trans (involving two or more chromosomes) domains is critical for proper development and normal cell proliferation [1–3]. (B) DNA segment interactions stabilized by cohesins (independent of CTCF) during S phase are critical for meiotic and mitotic sister chromatid tethering, chromosome condensation, and DNA repair [4–6].
Fig 2.
(A) Elongated coiled coil Smc1 and Smc3 proteins dimerize via hinge associations. (B) Smc1,3 become loosely tethered by Mcd1/Scc1/RAD21, which in turn recruits Pds5 and Scc3/SA1,2 (3 globular head structure). (C) and (D) Smc1,3 heads become tightly apposed and coiled coil domains zipper to form predominantly rodlike structures. Smc1,3 coiled coil domains can fold over into a C-clamp conformation to promote head–hinge association. Potential DNA entrapment sites are shown, but subunit dissociations (hinge–hinge, Smc1,3 ATPase heads, or Smc3-Mcd1/Scc1/Rad21) that allow entrapment, or whether there is a physiological role for C-clamp cohesins, remain hotly debated. (E) ATPase domains are composite structures that contain Walker A and B motifs from one Smc and D loop and C motif from the other Smc. (F) and (G) Hypothetical oligomerization models include intercohesin coiled coil or head–head binding, through which DNA segments (not shown) become tethered together. See text for references and further details.
Fig 3.
Multifaceted roles of cohesin.
Cohesin functions are separable through cell cycle (red: mitotic; green: interphase) and genetic manipulations. For instance, mutation of RAD61 suppresses only condensation defects, while mutation of ELG1 (mimicking overexpression of PCNA) suppresses only cohesion defects otherwise present in mitotic cells deficient in cohesin activation. Note that human paralogs ESCO1,2 (yeast Eco1/Ctf7) and Rad61/WAPL orthologs exhibit predominantly separate functions. See text for references.