Cohesin recruits the Esco1 acetyltransferase genome wide to repress transcription and promote cohesion in somatic cells

Rahman, Sadia; Ma, Jones; Jallepalli, Prasad V.

doi:10.1073/pnas.1505323112

Cited by 40 publications

(49 citation statements)

References 59 publications

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“…Smc3 acetylation can occur at low levels outside S phase and is regulated by the ATPase activity of cohesin (40,41). Although binding of Pds5 to cohesin does not require Smc3 acetylation in human cells, the Pds5-dependent binding of sororin to cohesin requires Smc3 acetylation (27).…”

Section: Discussionmentioning

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.

113

125

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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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Section: Discussionmentioning

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.

113

125

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“…First, budding and fission yeast have only one cohesin acetyltransferase, whereas vertebrate cells have two: ESCO1 and ESCO2. The human ESCO1 and ESCO2 show strikingly distinct patterns of chromatin association in somatic cells, directed by their divergent N-terminal motifs that are not conserved in budding yeast Eco1 (Hou and Zou 2005;Rahman et al 2015). Second, budding yeast is an exception regarding the mechanisms by which cohesin is removed and recycled from the chromosomes.…”

mentioning

confidence: 99%

“…In S. cerevisiae, cohesin removal depends entirely on cleavage of Scc1/Rad21 at anaphase by a protein called separase, whereas, in vertebrates, WAPL removes cohesin from chromosome arms during prophase as intact rings, and only a small pool of cohesin at centromeres remains to be cleaved by the protease separase at anaphase (Peters and Nishiyama 2012;Tedeschi et al 2013). Third, cohesin and ESCO1/2 play roles in controlling gene expression (Rahman et al 2015). These mechanisms are potentially different from budding yeast in which other coregulators of the cohesin function in transcription, such as CTCF, are missing (Peters and Nishiyama 2012).…”

mentioning

confidence: 99%

ESCO1/2's roles in chromosome structure and interphase chromatin organization

et al. 2017

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ESCO1/2 acetyltransferases mediating SMC3 acetylation and sister chromatid cohesion (SCC) are differentially required for genome integrity and development. Here we established chicken DT40 cell lines with mutations in ESCO1/2, SMC3 acetylation, and the cohesin remover WAPL. Both ESCO1 and ESCO2 promoted SCC, while ESCO2 was additionally and specifically required for proliferation and centromere integrity. ESCO1 overexpression fully suppressed the slow proliferation and centromeric separation phenotypes of esco2 cells but only partly suppressed its chromosome arm SCC defects. Concomitant inactivation of ESCO1 and ESCO2 caused lethality owing to compromised mitotic chromosome segregation. Neither wapl nor acetyl-mimicking smc3-QQ mutations rescued esco1 esco2 lethality. Notably, esco1 esco2 wapl conditional mutants showed very severe proliferation defects associated with catastrophic mitoses and also abnormal interphase chromatin organization patterns. The results indicate that cohesion establishment by vertebrate ESCO1/2 is linked to interphase chromatin architecture formation, a newly identified function of cohesin acetyltransferases that is both fundamentally and medically relevant.

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“…Indeed, cohesin acetylation can occur efficiently before and after DNA replication in Xenopus egg extracts [91]. In human cells, Esco1 has been shown to constitutively co-localize with and mediate the acetylation of cohesin at CTCF sites throughout the cell cycle [65,92]. This replication-independent cohesin acetylation mediates gene silencing [92].…”

Section: Establishment Of Sister Chromatid Cohesionmentioning

confidence: 99%

“…In human cells, Esco1 has been shown to constitutively co-localize with and mediate the acetylation of cohesin at CTCF sites throughout the cell cycle [65,92]. This replication-independent cohesin acetylation mediates gene silencing [92]. Thus, Smc3 acetylation is necessary but not sufficient for cohesion establishment.…”

Section: Establishment Of Sister Chromatid Cohesionmentioning

confidence: 99%

Regulation of sister chromatid cohesion during the mitotic cell cycle

2015

Sci. China Life Sci.

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Orderly execution of two critical events during the cell cycle--DNA replication and chromosome segregation--ensures the stable transmission of genetic materials. The cohesin complex physically connects sister chromatids during DNA replication in a process termed sister chromatid cohesion. Timely establishment and dissolution of sister chromatid cohesion is a prerequisite for accurate chromosome segregation, and is tight regulated by the cell cycle machinery and cohesin-associated proteins. In this review, we discuss recent progress in the molecular understanding of sister chromatid cohesion during the mitotic cell cycle.cell cycle, mitosis, sister chromatid cohesion, cohesin, cohesin loading, cohesin release, DNA replication, cohesion establishment Citation:Zheng G, Yu HT. Regulation of sister chromatid cohesion during the mitotic cell cycle. Sci China Life Sci, 2015Sci, , 58: 1089Sci, -1098Sci, , doi: 10.1007 During the cell cycle, DNA undergoes replication during S phase to generate two identical copies of each chromosome, called sister chromatids. During mitosis, sister chromatids are separated and partitioned evenly to the two daughter cells to maintain genomic stability. Cells receive too many or too few chromosomes become aneuploid. Aneuploidy can drive tumorigenesis in a context-dependent manner [1,2]. To prevent premature sister chromatid separation and ensure accurate chromosome segregation, sister chromatids are physically tethered to each other through the process of sister chromatid cohesion, as well as DNA catenation, from S phase till metaphase. Sister chromatid cohesion is mediated by the highly conserved ring-shaped cohesin complex, which topologically entraps chromosomes [3,4]. Cohesion establishment, maintenance, and removal at different cell cycle phases require a series of coordinated interactions between cohesin and its regulators (Figure 1). Cohesin is loaded onto DNA by the cohesin loader complex Scc2-Scc4 in telophase and early G1 [57]. At this stage, the chromatin-bound cohesin is highly dynamic, and can be released from chromosomes by the cohesin releasing factor Wapl, with the help of the scaffold protein Pds5 [811]. During S phase, the replicated sister chromatids are tethered by cohesin to establish sister chromatid cohesion. Cohesion establishment requires the acetylation of two adjacent, evolutionarily conserved lysines on Smc3 by the acetyltransferase Eco1 (Esco1/2 in vertebrates) [1217], and in metazoans, the subsequent recruitment of sororin to cohesin through Pds5 [1821]. Smc3 acetylation and sororin antagonize the cohesin-releasing activity of Wapl-Pds5, thereby stabilizing cohesin on chromosomes [17,21]. Finally, in mitosis, cohesin is released from chromosomes in a stepwise manner in vertebrates [22]. In early mitosis, Pds5-bound sororin is phosphorylated by mitotic kinases and dissociates from cohesin [21,2325]. Sororin dissociation allows Wapl to gain access to Pds5 and cohesin, releasing cohesin from chromosome arms. At centromeres,

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Cohesin recruits the Esco1 acetyltransferase genome wide to repress transcription and promote cohesion in somatic cells

Cited by 40 publications

References 59 publications

Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

ESCO1/2's roles in chromosome structure and interphase chromatin organization

Regulation of sister chromatid cohesion during the mitotic cell cycle

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