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Title: Structural evidence for Scc4-dependent localization of cohesin loading}
Article:
Abstract:
The cohesin ring holds newly replicated sister chromatids together until their separation at anaphase. Initiation of sister chromatid cohesion depends on a separate complex, Scc2NIPBL/Scc4Mau2( Scc2/4), which loads cohesin onto DNA and determines its localization across the genome. Proper cohesin loading is essential for cell division, and partial defects cause chromosome missegregation and aberrant transcriptional regulation, leading to severe developmental defects in multicellular organisms. We present here a crystal structure showing the interaction between Scc2 and Scc4. Scc4 is a TPR array that envelops an extended Scc2 peptide. Using budding yeast, we demonstrate that a conserved patch on the surface of Scc4 is required to recruit Scc2/4 to centromeres and to build pericentromeric cohesion. These findings reveal the role of Scc4 in determining the localization of cohesin loading and establish a molecular basis for Scc2/4 recruitment to centromeres.
Introduction:
Tight association between sister chromatids is crucial for successful chromosome segregation in eukaryotic cell division. Cohesin, a ring-shaped protein complex that wraps around sister chromatids( Gruber et al., 2003; Haering et al., 2008) is the molecular agent of sister chromatid cohesion, which persists from the time of DNA replication until anaphase. A distinct protein complex containing Scc2NIPBL and Scc4Mau2( Scc2/4) initiates linkage of cohesin with DNA( Ciosk et al., 2000), and an in vitro reconstitution of cohesin loading by Scc2/4 suggests that the product of this reaction is a topological protein–DNA linkage( Murayama and Uhlmann, 2013). In metazoans, cohesin deposition by Scc2/4 is required for normal development( Dorsett et al., 2005; Kawauchi et al., 2009), and mutations in NIPBL, the human homolog of Scc2, are dominant and causally linked to a severe developmental disorder, Cornelia de Lange Syndrome( CDLS)( Krantz et al., 2004). In addition to initiating a connection between cohesin and chromatin, Scc2/4 determines the timing and location of cohesin loading( Ciosk et al., 2000; Kogut et al., 2009). Cohesin enrichment at mitotic centromeres and pericentromeres results in tension across sister chromatids when paired kinetochores attach to opposite spindle microtubules( Tanaka, 2000). Mitotic spindle checkpoint signaling senses the tension between sister centromeres to ensure correct kinetochore–microtubule attachments( Stern and Murray, 2001). Defective centromeric cohesion therefore leads to elevated rates of chromosome missegregation( Eckert et al., 2007; Fernius and Marston, 2009). Centromeric cohesion depends on recruitment of Scc2/4 to centromeres in late G1/early S phase( Hu et al., 2011; Fernius et al., 2013). A group of conserved kinetochore proteins—the Ctf19 complex in yeast( homologous to the human CCAN)—participates in this recruitment pathway, along with the S phase kinase complex, DDK( Fernius and Marston, 2009; Hu et al., 2011; Natsume et al., 2013). Deletion of any of several Ctf19 complex members leads to impaired centromeric cohesion and chromosome missegregation( Eckert et al., 2007; Fernius and Marston, 2009; Ng et al., 2009; Hu et al., 2011), but whether individual components make direct contact with Scc2/4 is not yet known. The cohesin loading activity of Scc2/4 in vitro requires only Scc2( Murayama and Uhlmann, 2013). Scc4 is essential in yeast, however, and in humans, de novo Mau2Scc4 missense and nonsense mutations are significantly underrepresented in exome sequences, indicating that disruption of Mau2Scc4 function is probably dominant and lethal( Table 1). Thus, Scc2 activity in vivo must depend on Scc4 in ways not recapitulated by the in vitro loading reaction. We report here the structure of yeast Scc4 in complex with an N-terminal fragment of Scc2 and demonstrate that Scc4 determines cohesin localization through a conserved patch on its surface. These findings show that Scc4 targets cohesin loading to a specific genomic locus and that this function is separable from its essential role in establishing sister chromatid cohesion across the genome. 10. 7554/eLife. 06057. 019Table 1. De novo mutation profiles for human NIPBL and Mau2DOI: http://dx. doi. org/10. 7554/eLife. 06057. 019ObservedExpectedNIPBL Synonymous5858. 4 Missense88160. 9 Loss of function018. 4Mau2 Synonymous2526. 6 Missense1352. 7 Loss of function03. 8
Discussion:
Cohesin targeting to specific genomic locations is required in all species for robust centromeric cohesion and for tissue-specific transcriptional programs in multicellular organisms( Kawauchi et al., 2009; Fay et al., 2011). DNA sequences per se do not drive cohesin loading( Onn and Koshland, 2011; Murayama and Uhlmann, 2013). Instead, targeting likely depends on interactions between the loading complex and chromatin-associated factors. We have determined the structure of Scc4 bound to a minimal fragment of Scc2, and we have used this structure to derive separation of function alleles that uncouple cohesin loading from cohesin targeting to centromeres. These experiments demonstrate that cohesin targeting in yeast depends on Scc4. This finding is consistent with unpublished genetic evidence for an Scc4-dependent cohesin localization pathway( Nasmyth, personal communication). Because the pathway that targets cohesin to centromeres requires Scc4 residues that are, in some cases, invariant across diverse eukaryotes, we suggest that the Scc4-dependent cohesin targeting we describe is a general feature of the control of cohesin loading. Consistent with previous reports( Fernius et al., 2013; Natsume et al., 2013), we find that the centromeric enrichment of cohesin loading is not essential for viability and that arm cohesion is unaffected in strains in which this pathway is compromised. These results probably reflect two modes for cohesin loading: one that depends on a conserved patch of Scc4 and happens at centromeres, and a second opportunistic mode that happens everywhere on the chromosome and is sufficient to support viability in the absence of the first mode. If so, Scc4-conserved patch mutations would not eliminate cohesin loading but would redistribute loading events, resulting in similar cohesin levels at centromeres and on chromosome arms. This prediction is borne out both by strains bearing Scc4-conserved patch mutations and by strains lacking CHL4( Fernius and Marston, 2009). Recent reports have shown that cohesin targeting to specific locations along the chromosome arms of fission yeast( Mizuguchi et al., 2014) and flies( Oliveira et al., 2014) is critical for normal three-dimensional chromosome structure. In addition to findings from studies conducted in mammalian cells( Dowen et al., 2014), one of these reports( Mizuguchi et al., 2014) suggests that cohesin complexes residing at specified sites in the genome function in gene looping and in defining chromosome territories. Because our ChIP-seq experiments show that Scc4 directs cohesin localization to broad centromeric domains but does not affect the local distribution of cohesin peaks, we suggest that the Scc4-dependent localization pathway we discuss here is overlaid upon local determinants of cohesin positioning on chromosomes. These local determinants would be a second level of cohesin regulation, operating at roughly the resolution of the transcriptional units in yeast. Integration of these spatial cues with temporal cues, including the kinase activity of DDK, could then generate the final cohesin distribution observed in metaphase cells. The Scc4-conserved patch presents a possible explanation for how broad cohesin-dense domains may be specified by the cohesion-loading complex, and it provides a molecular foundation for the study of chromatin-associated factors, both known and unknown, that localize cohesin loading.
DNA replication copies the genetic information contained in a cell's chromosomes . A ring-like protein complex , cohesin , holds together each pair of newly-replicated chromosomes , known as ‘sister chromatids’ . When the cell divides , cohesin is cleaved; this allows sister chromatids to separate , so that each daughter cell receives one member of each sister chromatid pair and thereby inherits a full complement of genes . Defects in this process result in severe developmental abnormalities . Moreover , the genes that underlie this process are among the most frequently mutated in cancer . Cohesin is enriched at centromeres: the chromosomal points of attachment to the apparatus ( called the ‘mitotic spindle’ ) that segregates the sister chromatids into the daughter cells . The protein complex that loads cohesin onto chromosomes determines this preferential localization . The two components of the loading complex , Scc2 and Scc4 , associate as a 1:1 pair . Hinshaw et al . used a technique called X-ray crystallography to determine the structure of Scc4 bound with a large fragment of Scc2 . The result showed that the elongated Scc4 twists around the fragment of Scc2 , forming an extended groove . Scc2 snakes through the Scc4 groove and emerges at both ends . Hinshaw et al . then performed a series of experiments in yeast cells to probe how Scc4 determines the location at which cohesin loads onto chromosomes . These experiments revealed that a region on the surface of Scc4 targets both Scc4 and Scc2 to centromeres . The amino-acid sequence of this centromere-targeting patch on the surface of Scc4 is conserved across species . Thus , the mechanism by which Scc4 localizes cohesin to centromeres may be similar in all eukaryotic organisms .