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

ABSTRACT: The cohesin complex links DNA molecules and plays key roles in the organization, expression, repair, and segregation of eukaryotic genomes. In vertebrates the Esco1 and Esco2 acetyltransferases both modify cohesin’s Smc3 subunit to establish sister chromatid cohesion during S phase, but differ in their N-terminal domains and expression during development and across the cell cycle. Here we show that Esco1 and Esco2 also differ dramatically in their interaction with chromatin, as Esco1 is recruited by cohesin to over 11,000 sites, whereas Esco2 is infrequently enriched at REST/NRSF target genes. Esco1’s colocalization with cohesin occurs throughout the cell cycle and depends on two short motifs (the A-box and B-box) present in and unique to all Esco1 orthologs. Deleting either motif led to the derepression of Esco1-proximal genes and functional uncoupling of cohesion from Smc3 acetylation. In contrast, other mutations that preserved Esco1’s recruitment separated its roles in cohesion establishment and gene silencing. We conclude that Esco1 uses cohesin as both a substrate and a scaffold for coordinating multiple chromatin-based transactions in somatic cells. Total RNA was isolated after treatment with indicated siRNAs, or transfection reagent only for control samples. Samples for each group in triplicate were processed for Illumina bead arrays (Illumina HT-12) by the MSKCC genomics core facility according to manufacturer instructions.

ORGANISM(S): Homo sapiens

SUBMITTER: Jeffrey Zhao

PROVIDER: E-GEOD-71420 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Project description:The cohesin complex links DNA molecules and plays key roles in the organization, expression, repair, and segregation of eukaryotic genomes. In vertebrates the Esco1 and Esco2 acetyltransferases both modify cohesin’s Smc3 subunit to establish sister chromatid cohesion during S phase, but differ in their N-terminal domains and expression during development and across the cell cycle. Here we show that Esco1 and Esco2 also differ dramatically in their interaction with chromatin, as Esco1 is recruited by cohesin to over 11,000 sites, whereas Esco2 is infrequently enriched at REST/NRSF target genes. Esco1’s colocalization with cohesin occurs throughout the cell cycle and depends on two short motifs (the A-box and B-box) present in and unique to all Esco1 orthologs. Deleting either motif led to the derepression of Esco1-proximal genes and functional uncoupling of cohesion from Smc3 acetylation. In contrast, other mutations that preserved Esco1’s recruitment separated its roles in cohesion establishment and gene silencing. We conclude that Esco1 uses cohesin as both a substrate and a scaffold for coordinating multiple chromatin-based transactions in somatic cells.

2015-08-25 | GSE71420 | GEO

ATM-ESCO2-SMC3 axis regulates cohesin-dependent chromatin structure dynamics in response to DNA damage and safeguards genome integrity by promoting 53BP1 recruitment

Project description:53BP1 is primarily known as a key regulator in DNA double-strand break (DSB) repair. However, the mechanism of DSB-triggered cohesin modification-modulated chromatin structure on the recruitment of 53BP1 remains largely elusive. Here we identified acetyltransferase ESCO2 as a regulator for DSB-induced cohesin-dependent chromatin structure dynamics, which promotes 53BP1 recruitment. Mechanistically, in response to DNA damage, ATM phosphorylates ESCO2 S196 and T233. MDC1 recognizes phosphorylated ESCO2 and recruits ESCO2 to DSB sites. ESCO2-mediated acetylation of SMC3 stabilizes cohesin complex conformation and regulates the chromatin structure at DSB breaks, which is essential for the recruitment of 53BP1 and the formation of 53BP1 microdomains. Furthermore, depletion of ESCO2 in both colorectal cancer cells and xenografted nude mice sensitizes cancer cells to chemotherapeutic drugs. Collectively, our results reveal a molecular mechanism for the ATM-ESCO2-SMC3 axis in DSB repair and genome integrity maintenance with a vital role in chemotherapy response in colorectal cancer.

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The Smc3 deacetylase Hos1 closes the cohesin acetylation cycle

Project description:Cohesion between sister chromatids is mediated by the chromosomal cohesin complex. In budding yeast, cohesin is loaded onto chromosomes during the G1 phase of the cell cycle. During S-phase, the replication fork-associated acetyltransferase Eco1 acetylates the cohesin subunit Smc3 to promote establishment of sister chromatid cohesion. At the time of anaphase, Smc3 loses its acetylation again, but the Smc3 deacetylase and possible importance of Smc3 deacetylation are unknown. Here, we show that the class I histone deacetylase family member Hos1 is responsible for Smc3 deacetylation. Cohesin is protected from deacetylation while bound to chromosomes, but is deacetylated as soon as it dissociates from chromosomes following separase cleavage at anaphase onset. Non-acetylated Smc3 is required as a substrate for cohesion establishment in the following cell cycle. Our results complete the description of the Smc3 acetylation cycle and provide unexpected insight into the importance of de novo Smc3 acetylation for cohesion establishment.

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Sister chromatid cohesion establishment by acetylation

Project description:Cohesion between sister chromatids depends on the chromosomal cohesin complex and allows the spindle apparatus in mitosis to recognize replicated chromosomes for segregation into daughter cells. Sister chromatid cohesion is established concomitant with DNA replication, and requires the essential Eco1 protein, a replication fork-associated acetyl transferase. The mechanism by which Eco1 establishes sister chromatid cohesion is not known. Here, we show that the cohesin subunit Smc3 is acetylated in an Eco1-dependent manner during S phase to establish sister chromatid cohesion. We isolated spontaneous suppressors of the thermosensitive eco1-1 allele in budding yeast, and identified the suppressor mutations from the hybridization pattern of genomic DNA on oligonucleotide tiling arrays. An acetylation mimicking mutation of a conserved lysine in Smc3 to asparagine (K113N) makes Eco1 dispensable for cell growth, indicating that Smc3 acetylation is Eco1’s only essential function. We identified a second set of eco1-1 suppressor mutations in the budding yeast ortholog of the cohesin regulator Wapl (Wpl1/Rad61). Wapl destabilizes cohesin on chromosomes, and Eco1-dependent Smc3 acetylation during S-phase might render cohesin resistant to Wapl. Our results clarify the role of Eco1 in the establishment of sister chromatid cohesion, and suggest that Eco1 modifies cohesin to stabilize an Eco1-independent cohesion establishment reaction.

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Smc3 deacetylation by Hos1 facilitates efficient dissolution of sister chromatid cohesion during anaphase

Project description:Sister chromatid cohesion relies on cohesins, a group of proteins that forms a ring-shaped complex embracing sister chromatids. Cohesion is established during S phase and is removed when cohesin Scc1 is cleaved by the protease separase at anaphase onset. During this process, the cohesin subunit Smc3 undergoes a cycle of acetylation: Smc3 acetylation by Eco1 in S phase stabilizes cohesin association with chromosomes, and its deacetylation by Hos1 in anaphase allows re-use of Smc3 in the next cell cycle. Here we find that Smc3 deacetylation by Hos1 has a more immediate effect in early anaphase of budding yeast. Without Hos1, sister chromatid separation and segregation are significantly delayed. Smc3 deacetylation facilitates removal of cohesins from chromosomes, without changing the Scc1 cleavage efficiency, thus promoting dissolution of cohesion. This action is probably due to disengagement of Smc1–3 heads, prompted by de-repression of their ATPase activity. We suggest Scc1 cleavage per se is insufficient for efficient dissolution of cohesion in early anaphase, but subsequent Smc3 deacetylation, which is triggered by Scc1 cleavage, is also required.

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Conformational dynamics of cohesin/Scc2 loading complex are regulated by Smc3 acetylation and ATP association

Project description:The ring-shaped cohesin complex is the key player in sister chromatid cohesion, DNA repair, and gene transcription. The loading of cohesin to chromosomes requires the loader Scc2 and is regulated by ATP. This process is also hindered by Smc3 acetylation. However, the molecular mechanism behind this inhibition remains mysterious. Here we identify a novel configuration of Scc2 with pre-engaged cohesin and reveal dynamic conformations of the cohesin/Scc2 complex in the loading reaction. We demonstrate that Smc3 acetylation blocks the association of Scc2 with pre-engaged cohesin by impairing the interaction of Scc2 with Smc3’s head. Lastly, we show that ATP binding induces the cohesin/Scc2 complex to clamp DNA by promoting the interaction between Scc2 and Smc3 coiled-coil. Our results illuminate a dynamic reconfiguration of the cohesin/Scc2 complex during loading and indicate how Smc3 acetylation and ATP regulate this process.

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Cohesin releases DNA through asymmetric ATPase-driven ring opening

Project description:Cohesin stably holds together the sister chromatids from S phase until mitosis. To do so, cohesin must be protected against its cellular antagonist Wapl. Eco1 acetylates cohesinâs Smc3 subunit, which locks together the sister DNAs. We used yeast genetics to dissect how Wapl drives cohesin from chromatin and identified mutants of cohesin that are impaired in ATPase activity but remarkably confer robust cohesion that bypasses the need for the cohesin protectors Eco1 in yeast and Sororin in human cells. We uncover an unexpected functional asymmetry within the heart of cohesinâs highly conserved ABC-like ATPase machinery and show that an activity associated with one of cohesinâs two ATPase sites drives DNA release from cohesin rings. This key mechanism is conserved from yeast to humans. We propose that Eco1 locks cohesin rings around the sister chromatids by counteracting an asymmetric cohesin-associated ATPase activity. Effect of mutations in Smc1 and Smc3 on cohesin loading onto chromosomes

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Cohesin is involved in transcriptional repression of invasion-related genes

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