Cohesin and Its Regulation: On the Logic of X-Shaped Chromosomes

Haarhuis, Judith H.I.; Elbatsh, Ahmed M.O.; Rowland, Benjamin D.

doi:10.1016/j.devcel.2014.09.010

Cited by 134 publications

(153 citation statements)

References 120 publications

(208 reference statements)

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“…The anaphase-promoting complex or cyclosome (APC/C), along with its activator cell division cycle 20 (Cdc20), indirectly activates the protease separase through triggering the ubiquitination and degradation of the separase inhibitors, securin and cyclin B1 (3)(4)(5). Active separase then cleaves cohesin, leading to chromosome segregation (6,7). The separated chromatids are evenly partitioned into the two daughter cells through their attachment to the spindle.…”

mentioning

confidence: 99%

Structure of an intermediate conformer of the spindle checkpoint protein Mad2

Hara

Özkan

Sun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The spindle checkpoint senses unattached kinetochores during prometaphase and inhibits the anaphase-promoting complex or cyclosome (APC/C), thus ensuring accurate chromosome segregation. The checkpoint protein mitotic arrest deficient 2 (Mad2) is an unusual protein with multiple folded states. Mad2 adopts the closed conformation (C-Mad2) in a Mad1–Mad2 core complex. In mitosis, kinetochore-bound Mad1–C-Mad2 recruits latent, open Mad2 (O-Mad2) from the cytosol and converts it to an intermediate conformer (I-Mad2), which can then bind and inhibit the APC/C activator cell division cycle 20 (Cdc20) as C-Mad2. Here, we report the crystal structure and NMR analysis of I-Mad2 bound to C-Mad2. Although I-Mad2 retains the O-Mad2 fold in crystal and in solution, its core structural elements undergo discernible rigid-body movements and more closely resemble C-Mad2. Residues exhibiting methyl chemical shift changes in I-Mad2 form a contiguous, interior network that connects its C-Mad2–binding site to the conformationally malleable C-terminal region. Mutations of residues at the I-Mad2–C-Mad2 interface hinder I-Mad2 formation and impede the structural transition of Mad2. Our study provides insight into the conformational activation of Mad2 and establishes the basis of allosteric communication between two distal sites in Mad2.

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mentioning

confidence: 99%

Structure of an intermediate conformer of the spindle checkpoint protein Mad2

Hara

Özkan

Sun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Cohesin dynamics on chromosomes are regulated by a set of accessory proteins, including the Scc2-Scc4 loading complex and the releasing complex comprising Pds5 and winged apart-like protein (Wapl) (2,4,5). Scc2-Scc4 promotes the loading of cohesin onto chromosomes in telophase and G1 (15).…”

mentioning

confidence: 99%

Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

Kikuchi

Borek

Otwinowski

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The ring-shaped cohesin complex topologically entraps chromosomes and regulates chromosome segregation, transcription, and DNA repair. The cohesin core consists of the structural maintenance of chromosomes 1 and 3 (Smc1-Smc3) heterodimeric ATPase, the kleisin subunit sister chromatid cohesion 1 (Scc1) that links the two ATPase heads, and the Scc1-bound adaptor protein Scc3. The sister chromatid cohesion 2 and 4 (Scc2-Scc4) complex loads cohesin onto chromosomes. Mutations of cohesin and its regulators, including Scc2, cause human developmental diseases termed cohesinopathy. Here, we report the crystal structure of Chaetomium thermophilum (Ct) Scc2 and examine its interaction with cohesin. Similar to Scc3 and another Scc1-interacting cohesin regulator, precocious dissociation of sisters 5 (Pds5), Scc2 consists mostly of helical repeats that fold into a hook-shaped structure. Scc2 binds to Scc1 through an N-terminal region of Scc1 that overlaps with its Pds5-binding region. Many cohesinopathy mutations target conserved residues in Scc2 and diminish Ct Scc2 binding to Ct Scc1. Pds5 binding to Scc1 weakens the Scc2-Scc1 interaction. Our study defines a functionally important interaction between the kleisin subunit of cohesin and the hook of Scc2. Through competing with Scc2 for Scc1 binding, Pds5 might contribute to the release of Scc2 from loaded cohesin, freeing Scc2 for additional rounds of loading.transcription | cohesinopathy | X-ray crystallography | cohesin loading | HEAT repeat C ohesin consists of four core subunits: structural maintenance of chromosomes 1 and 3 (Smc1 and Smc3), and sister chromatid cohesion 1 and 3 (Scc1 and Scc3). (1-5). Smc1 and Smc3 are related ATPases that heterodimerize through their hinge domains. The C-terminal winged helix domain and the N-terminal helical domain (NHD) of Scc1 bind to the Smc1 ATPase head and a coiled-coil segment adjacent to the Smc3 ATPase head, respectively, forming a tripartite ring (6, 7). Scc3 contains Huntingtin-elongation factor 3-protein phosphatase 2A-TOR1 (HEAT) repeats, binds to the middle region of Scc1, and provides a landing pad for several cohesin regulators (8, 9). Cohesin can topologically trap DNA inside its ring (10), thereby regulating many facets of chromosome biology. During interphase, cohesin mediates the formation of chromosome loops that impact transcription (11). During S phase, cohesin physically links replicated chromosomes to establish sister-chromatid cohesion (12, 13), which is a prerequisite for faithful chromosome segregation during mitosis. Finally, cohesin contributes to homologydirected repair of DNA breaks, in part, through holding the sister chromatid in proximity of the breaks and presenting it as the repair template (14).For cohesin to accomplish these diverse tasks, its association with chromosomes has to be tightly controlled both spatially and temporally. Cohesin dynamics on chromosomes are regulated by a set of accessory proteins, including the Scc2-Scc4 loading complex and the releasing complex comprising Pds5 and wing...

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“…WAPL appears to play multiple roles in the cell, which can vary between organisms and between mitosis and meiosis (Haarhuis et al, 2014). Studies in yeast and animal cells have shown that WAPL in conjunction with PDS5 plays an important role in regulating the reversible binding of cohesin to chromosomes (Bernard et al, 2008;Sutani et al, 2009;Chan et al, 2012;LopezSerra et al, 2013).…”

Section: Proper Cohesin Levels Are Essential For Meiotic Chromosome Smentioning

confidence: 99%

The Opposing Actions of Arabidopsis CHROMOSOME TRANSMISSION FIDELITY7 and WINGS APART-LIKE1 and 2 Differ in Mitotic and Meiotic Cells

Bolaños-Villegas

Mitra

et al. 2016

Plant Cell

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Sister chromatid cohesion, which is mediated by the cohesin complex, is essential for the proper segregation of chromosomes during mitosis and meiosis. Stable binding of cohesin with chromosomes is regulated in part by the opposing actions of CTF7 (CHROMOSOME TRANSMISSION FIDELITY7) and WAPL (WINGS APART-LIKE). In this study, we characterized the interaction between Arabidopsis thaliana CTF7 and WAPL by conducting a detailed analysis of wapl1-1 wapl2 ctf7 plants. ctf7 plants exhibit major defects in vegetative growth and development and are completely sterile. Inactivation of WAPL restores normal growth, mitosis, and some fertility to ctf7 plants. This shows that the CTF7/WAPL cohesin system is not essential for mitosis in vegetative cells and suggests that plants may contain a second mechanism to regulate mitotic cohesin. WAPL inactivation restores cohesin binding and suppresses ctf7-associated meiotic cohesion defects, demonstrating that WAPL and CTF7 function as antagonists to regulate meiotic sister chromatid cohesion. The ctf7 mutation only had a minor effect on wapl-associated defects in chromosome condensation and centromere association. These results demonstrate that WAPL has additional roles that are independent of its role in regulating chromatin-bound cohesin.

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Cohesin and Its Regulation: On the Logic of X-Shaped Chromosomes

Cited by 134 publications

References 120 publications

Structure of an intermediate conformer of the spindle checkpoint protein Mad2

Structure of an intermediate conformer of the spindle checkpoint protein Mad2

Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

The Opposing Actions of Arabidopsis CHROMOSOME TRANSMISSION FIDELITY7 and WINGS APART-LIKE1 and 2 Differ in Mitotic and Meiotic Cells

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