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MicroRNA-449a inhibits triple negative breast cancer by disturbing DNA repair and chromatid separation

ABSTRACT: MicroRNA-449a inhibits triple negative breast cancer by disturbing DNA repair and chromatid separation

PROVIDER: PRJNA835447 | ENA |

REPOSITORIES: ENA

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MicroRNA-449a inhibits triple negative breast cancer by disturbing DNA repair and chromatid separation

Project description:To identify target genes of microRNA-449a in triple negative breast cancer (TNBC) we transfected the TNBC cell line HCC38 with miRNA449a mimics.

2022-05-06 | GSE202316 | GEO

MicroRNA-449a Inhibits Triple Negative Breast Cancer by Disturbing DNA Repair and Chromatid Separation.

Project description:Chromosomal instability (CIN) can be a driver of tumorigenesis but is also a promising therapeutic target for cancer associated with poor prognosis such as triple negative breast cancer (TNBC). The treatment of TNBC cells with defects in DNA repair genes with poly(ADP-ribose) polymerase inhibitor (PARPi) massively increases CIN, resulting in apoptosis. Here, we identified a previously unknown role of microRNA-449a in CIN. The transfection of TNBC cell lines HCC38, HCC1937 and HCC1395 with microRNA-449a mimics led to induced apoptosis, reduced cell proliferation, and reduced expression of genes in homology directed repair (HDR) in microarray analyses. EME1 was identified as a new target gene by immunoprecipitation and luciferase assays. The reduced expression of EME1 led to an increased frequency of ultrafine bridges, 53BP1 foci, and micronuclei. The induced expression of microRNA-449a elevated CIN beyond tolerable levels and induced apoptosis in TNBC cell lines by two different mechanisms: (I) promoting chromatid mis-segregation by targeting endonuclease EME1 and (II) inhibiting HDR by downregulating key players of the HDR network such as E2F3, BIRC5, BRCA2 and RAD51. The ectopic expression of microRNA-449a enhanced the toxic effect of PARPi in cells with pathogenic germline BRCA1 variants. The newly identified role makes microRNA-449a an interesting therapeutic target for TNBC.

| S-EPMC9102308 | biostudies-literature

ASXL1 Interacts with the Cohesin Complex to Maintain Chromatid Separation and Gene Expression for Normal Hematopoiesis [RNA-Seq]

Project description:ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice, however, the underlying molecular mechanisms remain unclear. Here, we report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromotid segregation and to regulate gene expression. Loss of Asxl1 impairs the cohesin function as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. ChIP-seq data revealed that ASXL1, RAD21 and SMC1A share 93% of genomic binding sites at promoter regions in lineage-cKit+ (LK) cells. We have showed that loss of Asxl1 reduced the genome binding of RAD21 and SMC1A, and altered the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and to regulate gene expression in hematopoietic cells.

2017-02-24 | GSE83961 | GEO

ASXL1 Interacts with the Cohesin Complex to Maintain Chromatid Separation and Gene Expression for Normal Hematopoiesis [ChIP-Seq]

2017-02-24 | GSE83960 | GEO

ASXL1 Interacts with the Cohesin Complex to Maintain Chromatid Separation and Gene Expression for Normal Hematopoiesis

Project description:ASXL1 Interacts with the Cohesin Complex to Maintain Chromatid Separation and Gene Expression for Normal Hematopoiesis

| PRJNA327559 | ENA

Dihydroartemisinin inhibits the proliferation of multiple myeloma cancer stem cells via disturbing nuclear lamina and chromatin architecture

Project description:Dihydroartemisinin inhibits the proliferation of multiple myeloma cancer stem cells via disturbing nuclear lamina and chromatin architecture

| PRJNA667951 | ENA

Targeted interference of sin3a-tgif1 function by SID decoy treatment inhibits WNT signaling and invasion in triple negative breast cancer cells

Project description:Targeted interference of sin3a-tgif1 function by SID decoy treatment inhibits WNT signaling and invasion in triple negative breast cancer cells. MDA-MB-231 cells were treated with scrambled SID control, 2.5ÂµM SID peptide or untreated for 24h. Sub-confluent cultures of MDA-MB-231 cells were treated with scrambled SID control, 2.5ÂµM SID peptide or untreated for 24h. Experiments were performed as three independent replicates.

2016-07-21 | E-GEOD-84648 | biostudies-arrayexpress

Targeted interference of sin3a-tgif1 function by SID decoy treatment inhibits WNT signaling and invasion in triple negative breast cancer cells

2016-07-21 | GSE84648 | GEO

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.

2017-11-02 | GSE96841 | GEO

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.

2008-07-24 | GSE11527 | GEO

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