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Condensin Engages Chromatin

Given the enormous lengths of eukaryotic DNA molecules, the compaction achieved by assembling them around nucleosomes is insufficient for allowing their successful partitioning by the mitotic spindle during cell divisions. Central to the formation of a correctly structured mitotic chromosome is the action of a multisubunit protein complex named condensin. In the absence of condensin, sister chromatids frequently fail to segregate completely to the cell poles. The resulting segregation defects are thought to give rise to aneuploidies, which are characteristic of most cancer cells. In addition to organizing chromosomes during mitosis, condensin complexes also play roles in the regulation of gene expression and DNA damage repair. Despite condensin’s vast range of activities, our current understanding of the molecular basis for its mode of action is still very limited. A key step forward in deciphering condensin’s mechanism is to find out how the complex is recruited to chromosomes. While none of the five subunits of the ~650 kDa complex contain obvious DNA binding motifs, their three-dimensional arrangement in the complex can probably provide important clues to condensin function. Condensin’s structural maintenance of chromosomes (SMC) subunits Smc2 and Smc4 fold into long rod-shaped structures with a heterodimerization domain at one end of an antiparallel intramolecular coiled coil and a globular ABC-ATPase domain at the other end. A third subunit of the kleisin protein family binds to both ATPase domains and at the same time to two other subunits, which are predicted to be largely composed of HEAT repeat motifs (Figure 1). While yeast cells express only a single condensin complex, multicellular organisms express at least two isoforms of condensin that differ in the identity of their non-SMC subunits and are named condensin I and II. The ring-shaped arrangement of the Smc2–Smc4 and kleisin subunits has led to the proposal that condensin may associate with chromatin fibers by encircling them. The findings that either DNA linearization or directed site-specific proteolytic cleavage of the kleisin subunit abolished the association between condensin and small circular chromosomes are consistent with the idea that condensin rings can entrap and slide along chromatin fibers, yet this idea is still under debate. A number of experiments also suggest that condensin is able to make direct contacts with the DNA double helix in vitro, possibly through its Smc2–Smc4 dimerization domains. How condensin is targeted to chromosomes at the right place and at the right time remained nevertheless poorly understood. A recent paper by Watanabe and colleagues now explains how condensin complexes are recruited to chromosomes. The authors found that core histone proteins copurified with condensin complexes that were isolated from mammalian chromatin fractions. Using purified components, they showed that the condensin I g-kleisin subunit (but not the condensin II b-kleisin) and the fission yeast kleisin subunit bound to histones H2A and H2A.Z. This raises the possibility that interactions with nucleosomes tether condensin to chromosomes. Consistent with this hypothesis, condensin had been found to bind less stably to mitotic chromosomes in fission yeast cells lacking H2A.Z. Furthermore, H2A.Z depletion using RNAi moderately reduced condensin I staining on human chromosomes. Condensin’s association with nucleosomes may not be limited to the binding of its kleisin subunit to H2A-type histones, since a previous study already suggested that one of the two HEAT repeat subunits of human condensin I binds to histones H1 and H3. Figure 1. Three steps of condensin binding to chromosomes. A) Recruiter proteins, including the Pcs1–Mde4 subunits of the monopolin complex or parts of the TFIIIC complex direct condensin binding to the centromeres or chromosome arms, respectively. B) Engagement of condensin with chromosomes requires docking to H2A-type histone proteins. C) Stable association of condensin with a chromosome may require loading proteins such as the Scc2–Scc4 complex. The order of A–C is not defined.