scholarly journals Esco1 and Esco2 regulate distinct cohesin functions during cell cycle progression

2017 ◽  
Vol 114 (37) ◽  
pp. 9906-9911 ◽  
Author(s):  
Reem M. Alomer ◽  
Eulália M. L. da Silva ◽  
Jingrong Chen ◽  
Katarzyna M. Piekarz ◽  
Katherine McDonald ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Cell Cycle Progression ◽  
Loop Formation ◽  
Cycle Progression ◽  
Sister Chromatids ◽  
Dependent Inactivation ◽  
Chromatid Cohesion ◽  
N Terminus ◽  
Dependent Modification ◽  
Unique Ability

Sister chromatids are tethered together by the cohesin complex from the time they are made until their separation at anaphase. The ability of cohesin to tether sister chromatids together depends on acetylation of its Smc3 subunit by members of the Eco1 family of cohesin acetyltransferases. Vertebrates express two orthologs of Eco1, called Esco1 and Esco2, both of which are capable of modifying Smc3, but their relative contributions to sister chromatid cohesion are unknown. We therefore set out to determine the precise contributions of Esco1 and Esco2 to cohesion in vertebrate cells. Here we show that cohesion establishment is critically dependent upon Esco2. Although most Smc3 acetylation is Esco1 dependent, inactivation of the ESCO1 gene has little effect on mitotic cohesion. The unique ability of Esco2 to promote cohesion is mediated by sequences in the N terminus of the protein. We propose that Esco1-dependent modification of Smc3 regulates almost exclusively the noncohesive activities of cohesin, such as DNA repair, transcriptional control, chromosome loop formation, and/or stabilization. Collectively, our data indicate that Esco1 and Esco2 contribute to distinct and separable activities of cohesin in vertebrate cells.

scholarly journals Multivalent interaction of ESCO2 with the replication machinery is required for sister chromatid cohesion in vertebrates

2019 ◽  
Vol 117 (2) ◽  
pp. 1081-1089 ◽  
Author(s):  
Dawn Bender ◽  
Eulália Maria Lima Da Silva ◽  
Jingrong Chen ◽  
Annelise Poss ◽  
Lauren Gawey ◽  
...  
Keyword(s):  
Dna Replication ◽  
Sister Chromatid ◽  
Sister Chromatid Cohesion ◽  
Replication Machinery ◽  
Replicative Helicase ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
N Terminus ◽  
Mcm Complex ◽  
Unique Ability

The tethering together of sister chromatids by the cohesin complex ensures their accurate alignment and segregation during cell division. In vertebrates, sister chromatid cohesion requires the activity of the ESCO2 acetyltransferase, which modifies the Smc3 subunit of cohesin. It was shown recently that ESCO2 promotes cohesion through interaction with the MCM replicative helicase. However, ESCO2 does not significantly colocalize with the MCM complex, suggesting there are additional interactions important for ESCO2 function. Here we show that ESCO2 is recruited to replication factories, sites of DNA replication, through interaction with PCNA. We show that ESCO2 contains multiple PCNA-interaction motifs in its N terminus, each of which is essential to its ability to establish cohesion. We propose that multiple PCNA-interaction motifs embedded in a largely flexible and disordered region of the protein underlie the unique ability of ESCO2 to establish cohesion between sister chromatids precisely as they are born during DNA replication.

scholarly journals SUMOylation targets shugoshin to stabilize sister kinetochore biorientation

2019 ◽  
Author(s):  
Xue Bessie Su ◽  
Menglu Wang ◽  
Claudia Schaffner ◽  
Dean Clift ◽  
Olga O. Nerusheva ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Cell Cycle Progression ◽  
Aurora B ◽  
Cycle Progression ◽  
Anaphase Onset ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Sister Kinetochore ◽  
Phosphatase 2A ◽  
Segregation Of Chromosomes

AbstractThe accurate segregation of chromosomes during mitosis relies on the attachment of sister chromatids to microtubules from opposite poles, called biorientation. Sister chromatid cohesion resists microtubule forces, generating tension which provides the signal that biorientation has occurred. How tension silences the surveillance pathways that prevent cell cycle progression and correct erroneous kinetochore-microtubule remains unclear. Here we identify SUMOylation as a mechanism that promotes anaphase onset upon biorientation. SUMO ligases modify the tension-sensing pericentromere-localized chromatin protein, shugoshin, to stabilize bioriented sister kinetochore-microtubule attachments. In the absence of SUMOylation, Aurora B kinase removal from kinetochores is delayed. Shugoshin SUMOylation prevents its binding to protein phosphatase 2A (PP2A) and release of this interaction is important for stabilizing sister kinetochore biorientation. We propose that SUMOylation modulates the kinase-phosphatase balance within pericentromeres to inactivate the error correction machinery, thereby allowing anaphase entry in response to biorientation.

scholarly journals SUMOylation stabilizes sister kinetochore biorientation to allow timely anaphase

2021 ◽  
Vol 220 (7) ◽  
Author(s):  
Xue Bessie Su ◽  
Menglu Wang ◽  
Claudia Schaffner ◽  
Olga O. Nerusheva ◽  
Dean Clift ◽  
...  
Keyword(s):  
Error Correction ◽  
Protein Phosphatase ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Anaphase Onset ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Sister Kinetochore ◽  
Phosphatase 2A ◽  
Chromosome Passenger Complex

During mitosis, sister chromatids attach to microtubules from opposite poles, called biorientation. Sister chromatid cohesion resists microtubule forces, generating tension, which provides the signal that biorientation has occurred. How tension silences the surveillance pathways that prevent cell cycle progression and correct erroneous kinetochore–microtubule attachments remains unclear. Here we show that SUMOylation dampens error correction to allow stable sister kinetochore biorientation and timely anaphase onset. The Siz1/Siz2 SUMO ligases modify the pericentromere-localized shugoshin (Sgo1) protein before its tension-dependent release from chromatin. Sgo1 SUMOylation reduces its binding to protein phosphatase 2A (PP2A), and weakening of this interaction is important for stable biorientation. Unstable biorientation in SUMO-deficient cells is associated with persistence of the chromosome passenger complex (CPC) at centromeres, and SUMOylation of CPC subunit Bir1 also contributes to timely anaphase onset. We propose that SUMOylation acts in a combinatorial manner to facilitate dismantling of the error correction machinery within pericentromeres and thereby sharpen the metaphase–anaphase transition.

PTTG has a Dual Role of Promotion-Inhibition in the Development of Pituitary Adenomas

2019 ◽  
Vol 26 (11) ◽  
pp. 800-818
Author(s):  
Zujian Xiong ◽  
Xuejun Li ◽  
Qi Yang
Keyword(s):  
Cell Cycle ◽  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Cell Cycle Progression ◽  
Key Factors ◽  
Cycle Progression ◽  
Sister Chromatids ◽  
Regulation Of Cell Cycle ◽  
Late Stages

Pituitary Tumor Transforming Gene (PTTG) of human is known as a checkpoint gene in the middle and late stages of mitosis, and is also a proto-oncogene that promotes cell cycle progression. In the nucleus, PTTG works as securin in controlling the mid-term segregation of sister chromatids. Overexpression of PTTG, entering the nucleus with the help of PBF in pituitary adenomas, participates in the regulation of cell cycle, interferes with DNA repair, induces genetic instability, transactivates FGF-2 and VEGF and promotes angiogenesis and tumor invasion. Simultaneously, overexpression of PTTG induces tumor cell senescence through the DNA damage pathway, making pituitary adenoma possessing the potential self-limiting ability. To elucidate the mechanism of PTTG in the regulation of pituitary adenomas, we focus on both the positive and negative function of PTTG and find out key factors interacted with PTTG in pituitary adenomas. Furthermore, we discuss other possible mechanisms correlate with PTTG in pituitary adenoma initiation and development and the potential value of PTTG in clinical treatment.

SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 723-735 ◽  
Author(s):  
Hedia Chagraoui ◽  
Mira Kassouf ◽  
Sreemoti Banerjee ◽  
Nicolas Goardon ◽  
Kevin Clark ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcriptional Control ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Loss Of Function ◽  
Cycle Progression ◽  
Cell Cycle Regulator ◽  
Nuclear Changes ◽  
Cytoplasmic Maturation

Abstract Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in loss-of-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genome-wide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Scl-mutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation.

scholarly journals Loss of ISWI ATPase SMARCA5 (SNF2H) in Acute Myeloid Leukemia Cells Inhibits Proliferation and Chromatid Cohesion

2020 ◽  
Vol 21 (6) ◽  
pp. 2073
Author(s):  
Tomas Zikmund ◽  
Helena Paszekova ◽  
Juraj Kokavec ◽  
Paul Kerbs ◽  
Shefali Thakur ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Cycle Progression ◽  
Mitotic Division ◽  
Cycle Progression ◽  
Hematopoietic Stem ◽  
Chromatid Cohesion ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

ISWI chromatin remodeling ATPase SMARCA5 (SNF2H) is a well-known factor for its role in regulation of DNA access via nucleosome sliding and assembly. SMARCA5 transcriptionally inhibits the myeloid master regulator PU.1. Upregulation of SMARCA5 was previously observed in CD34+ hematopoietic progenitors of acute myeloid leukemia (AML) patients. Since high levels of SMARCA5 are necessary for intensive cell proliferation and cell cycle progression of developing hematopoietic stem and progenitor cells in mice, we reasoned that removal of SMARCA5 enzymatic activity could affect the cycling or undifferentiated state of leukemic progenitor-like clones. Indeed, we observed that CRISPR/cas9-mediated SMARCA5 knockout in AML cell lines (S5KO) inhibited the cell cycle progression. We also observed that the SMARCA5 deletion induced karyorrhexis and nuclear budding as well as increased the ploidy, indicating its role in mitotic division of AML cells. The cytogenetic analysis of S5KO cells revealed the premature chromatid separation. We conclude that deleting SMARCA5 in AML blocks leukemic proliferation and chromatid cohesion.

scholarly journals Multivalent interaction of ESCO2 with the replication machinery is required for cohesion

2019 ◽  
Author(s):  
Dawn Bender ◽  
Eulália Maria Lima Da Silva ◽  
Jingrong Chen ◽  
Annelise Poss ◽  
Lauren Gawey ◽  
...  
Keyword(s):  
Cell Division ◽  
Dna Replication ◽  
Cohesin Complex ◽  
Replication Machinery ◽  
Replicative Helicase ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Mcm Helicase ◽  
N Terminus ◽  
Processivity Factor

AbstractThe tethering together of sister chromatids by the cohesin complex ensures their accurate alignment and segregation during cell division. In vertebrates, the establishment of cohesion between sister chromatids requires the activity of the ESCO2 acetyltransferase, which modifies the Smc3 subunit of cohesin. It was shown recently that ESCO2 promotes cohesion through interaction with the MCM replicative helicase. However, ESCO2 does not significantly colocalize with the MCM helicase, suggesting there may be additional interactions that are important for ESCO2 function. Here we show that ESCO2 is recruited to replication factories, the sites of DNA replication. We show that ESCO2 contains multiple conserved PCNA-interaction motifs in its N-terminus, and that each of these motifs are essential to ESCO2’s ability to establish sister chromatid cohesion. We propose that multiple PCNA interaction motifs embedded in a largely flexible and disordered region of the protein underlie the ability of ESCO2 to establish cohesion between sister chromatids precisely as they are born during DNA replication.SummaryCohesin modification by the ESCO2 acetyltransferase is required for cohesion between sister chromatids. Here we identify multiple motifs in ESCO2 that mediate its interaction with the replication processivity factor PCNA, and show that their mutation abrogates the ability of ESCO2 to ensure cohesion.

scholarly journals Unusual proliferation arrest and transcriptional control properties of a newly discovered E2F family member, E2F-6

1998 ◽  
Vol 95 (16) ◽  
pp. 9190-9195 ◽  
Author(s):  
Stefan Gaubatz ◽  
Jason G. Wood ◽  
David M. Livingston
Keyword(s):  
Cell Cycle ◽  
Transcriptional Control ◽  
Cell Cycle Progression ◽  
Specific Effect ◽  
3T3 Cells ◽  
Cycle Progression ◽  
E2f Transcription Factors ◽  
Regulation Of Cell Cycle ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

E2F transcription factors play an important role in the regulation of cell cycle progression. We report here the cloning and characterization of an additional member of this family, E2F-6. E2F-6 lacks pocket protein binding and transactivation domains, and it is a potent transcriptional repressor that contains a modular repression domain at its carboxyl terminus. Overproduction of E2F-6 had no specific effect on cell cycle progression in asynchronously growing Saos2 and NIH 3T3 cells, but it inhibited entry into S phase of NIH 3T3 cells stimulated to exit G0. Taken together, these data suggest that E2F-6 can regulate a subset of E2F-dependent genes whose products are required for entry into the cell cycle but not for normal cell cycle progression.

Localization of two mammalian cyclin dependent kinases during mammalian meiosis

2001 ◽  
Vol 114 (4) ◽  
pp. 685-693 ◽  
Author(s):  
T. Ashley ◽  
D. Walpita ◽  
DG de Rooij
Keyword(s):  
Cell Cycle Progression ◽  
Protein A ◽  
Mitotic Cell ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases ◽  
Meiotic Progression ◽  
Sister Chromatids ◽  
Reciprocal Recombination ◽  
Repair Protein ◽  
Mismatch Repair Protein

Mammalian meiotic progression, like mitotic cell cycle progression, is regulated by cyclins and cyclin dependent kinases (CDKs). However, the unique requirements of meiosis (homologous synapsis, reciprocal recombination and the dual divisions that segregate first homologues, then sister chromatids) have led to different patterns of CDK expression. Here we show that Cdk4 colocalizes with replication protein A (RPA) on the synaptonemal complexes (SCs) of newly synapsed axes of homologously pairing bivalents, but disappears from these axes by mid-pachynema. The switch from the mitotic pattern of expression occurs during the last two spermatogonial divisions. Cdk2 colocalizes with MLH1, a mismatch repair protein at sites of reciprocal recombination in mid-late pachynema. In addition Cdk2 localizes to the telomeres of chromosomal bivalents throughout meiotic prophase. The mitotic pattern of expression of Cdk2 remains unchanged throughout the spermatogonial divisions, but is altered in meiosis of the spermatocytes.

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